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COLUMBIA  LIBRARIES  OFFSITE 

HEALTH  SCIENCES  STANDARD 


t  of  Lectures  on  Tumors 


HX00035572 


GIVEN   UNDER  THE  AUSPICES  OF  THE 


'CANCER  COMMISSION  OF  HARVARD 
UNIVERSITY 

(Founded  by  Car    'ne  Brewer  Croft,  June  16,   1899) 


MEDICAL  SCHOOL  OF  HARVARD  UNIVERSITY 

BOSTON,  MASS. 

1909 


T^IlGS 


c)  I 


K'^G 


S^fier^nr^  Htbrarg 


A  Course  of  Lectures  on  Tumors 


GIVEN   UNDER  THE  AUSPICES  OF  THE 


CANCER  COMMISSION  OF  HARVARD 
UNIVERSITY 

(Founded  by  Caroline  Brewer  Croft,  June  16,    1899) 


MEDICAL  SCHOOL  OF  HARVARD  UNIVERSITY 

BOSTON,  MASS. 

1909 


THE   CANCER   COMMISSION   OF  HARVARD  UNIVERSITY 

(Founded  by  Caroline  Brewer  Croft,  June  16,  1899) 

Medical  School  of  Harvard  University 

Boston,  Mass. 


J.  Collins  Warben,  Chairman. 

Henby  K.  Oliver,    J.  Collins  Warben, 
For  the  Caroline  Breiver  Croft  Fund. 

Henby  P.  Walcott,   Abthur  T.  Cabot, 
For  the  Corporation  of  Harvard  College. 

William  T.  Councilman,    Theobald  Smith, 
For  the  Harvard  Medical  School. 

E.  E.  Tyzzek,  Director. 

RoBEBT  B.  Greenough,  Secretary. 


CONTENTS. 


PAGE 

The  Bearings  of  the  Experimental  Investigation  of  Tumors  on 
THE  Tumor  Problem  in  General. 

Dr.  E.  E.  Tyzzer,  Boston 5 

The  Classification  of  Tumors. 

Dr.  F.  B.  Mallory,  Boston 19 

The  Physiological  Pathology  of  Intracranial  Tumors. 

Dr.  Harvey  Gushing,  Baltimore 23 

The  Etiology  of  Tumors  Considered  from  Our  Knowledge  op 
Congenital  Tumors  and  Tumors  following  Repeated  Injuries. 

Dr.  S.  B.  Wolbach,  Albany 47 

The  Problem  of  Cancer  Considered  from  the  Standpoint  of 
Immunity. 

Dr.  F.  P.  Gay,  Boston 65 


The  Bearings  of  the   Experimental  Investigation  of 
Tumors  on  the  Tumor  Problem  in  General.* 

BY  E.  E.  TYZZER,  M.D., 

BOSTON,    MASS., 
Assistant  Professor  of  Pathology,  Harvard  Medical  School. 

The  activity  at  present  shown  in  the  investigation  of  tumors 
is  amply  justified  by  the  importance  of  this  problem  to  every 
civilized  people.  In  the  case  of  the  infectious  diseases  there  is 
always  the  possibility  of  the  development  of  a  considerable 
degree  of  racial  immunity  through  the  survival  of  the  more 
resistant  individuals.  This  is  shown  by  the  fact  that  when 
certain  of  the  infectious  diseases  are  conveyed  for  the  first  time 
to  isolated  tribes,  the  latter  succumb  in  far  greater  numbers 
than  is  usual  in  races  accustomed  to  these  diseases.  The 
destruction  of  certain  individuals  by  malignant  tumors,  how- 
ever, fails  to  produce  racial  exemption,  since  such  tumors  most 
frequently  occur  after  the  reproductive  period  is  past. 

The  statement  of  Bashford,^  that  in  the  deaths  of  males  above 
thirty-five  years  of  age  one  in  eleven  dies  of  cancer,  while  in  the 
deaths  of  females  of  similar  age  the  ratio  is  one  to  eight,  indi- 
cates the  frequency  of  malignant  disease. 

The  elucidation  of  the  etiology,  the  early  recognition  and  the 
cure  of  tumors  constitute  the  more  important  goals  toward 
which  tumor  investigation  is  directed.  The  etiology  of  tumors, 
for  a  long  time  the  stumbling  block  of  pathologists,  has  been 
a  subject  for  philosophical  quite  as  much  as  for  scientific 
consideration. 

A  great  variety  of  methods  have,  however,  been  applied  to 
its  investigation.  The  pathological  anatomist  has  made  clear 
the  nature  of  tumors,  —  that  they  consist  of  tissues  more  or 
less  atypical  in  structure,  but  similar  to  the  tissues  of  the  species 
in  which  they  occur,  — that  in  general  they  possess  powers  of 
unlimited  growth,  —  and  that  they  serve  no  useful  purpose  in 
the  organism,  but  often  grow  at  the  latter's  expense.     Like 

*  A  lecture  under  the  auspices  of  the  Cancer  Commission  of  Harvard  University. 
1  Third  scientific  report  of  the  Imperial  Research  Fund,  1908. 


6  TYZZER. 

other  tissues,  they  are  composed  either  of  cells,  or  of  cells 
associated  with  intercellular  substance.  It  has  been  found 
that  the  rapidly-growing  and  more  malignant  tumors  are,  as  a 
rule,  more  cellular,  whereas  many  of  the  slowly-growing  tumors 
possess  a  large  amount  of  intercellular  substance.  The  number 
of  cell  divisions  present  are  also  taken  as  an  index  of  the  rate 
of  growth. 

The  employment  of  bacteriological  methods  has  resulted  in 
the  isolation  of  various  organisms  by  different  investigators. 
None  of  the  bacteria  or  yeasts  found  have  been  shown  to  have 
any  causal  relation  to  the  development  of  tumors,  and  their 
presence  was  probably  in  all  instances  due  either  to  co-existing 
infections  or  to  secondary  invasion.  Subsequent  endeavors 
to  discover  by  the  histological  study  of  tumor  tissue  a  causative 
parasite  have  resulted  in  descriptions  of  protozoa  of  almost 
every  known  as  well  as  of  some  unfamiliar  types.  In  a  former- 
report  of  the  Harvard  Cancer  Commission,  attention  was  called 
to  the  occurrence  of  similar  objects  in  non-cancerous  tissues,, 
and  evidence  was  found  strongly  indicating  that  they  were  not 
of  the  nature  of  parasites.  More  recently,  the  presence  of 
spirochetse  in  mouse  tumors  was  given,  in  the  absence  of  any 
control  observations,  rather  undue  importance.  I  have  been 
able  to  demonstrate  in  refractory  mice,  months  after  the  last 
inoculation  of  tumor  tissue,  large  numbers  of  spirochetes  mor- 
phologically identical  with  those  occurring  in  tumor  mice. 
The  same  organisms  were  also  found  in  small  numbers  in  unin- 
oculated  mice  without  tumors.  As  a  last  resort,  cancer  is  now 
ascribed  by  certain  adherents  of  the  parasitic  theory  to  an  ultra- 
microscopic  organism.  It  is  claimed  by  Salvin,  Moore  and 
Walker  that  after  freezing  and  grinding  mouse  tumor  tissue 
with  liquid  air,  a  procedure  which  it  is  presumed  destroys  the 
epithelial  cells,  the  resulting  material  is  still  capable  of  producing 
tumors  on  inoculation  into  other  mice.  This  would  amount, 
then,  to  the  separation  of  a  virus  from  the  tumor  tissue,  an 
observation  which  finds  no  supj)ort  in  the  results  of  most  other 
investigators  who  have  worked  with  the  inoculable  tumors  of 
mice.  After  the  filtration  of  an  emulsion  of  tumor  tissue 
through  ordinary  filter  paper,  the  inoculation  of  the  filtrate  has 
been  attended  with  negative  results.  If  the  tissue  of  inoculable 
tumors  is  kept  at  room  temperature  on  its  removal  from  the 


TYZZER.  7 

body  it  soon  loses  its  property  of  producing  tumors  on  inocula- 
tion, and  this  change  takes  place  still  more  rapidly  if  incubated 
at  body  temperature. 

The  theories  concerning  the  origin  of  tumors  are  so  numerous 
that  they  will  be  no  more  than  outlined  in  this  paper.  Thiersch 
and  Waldeyer  believed  that  there  existed  between  epithelium 
and  connective  tissue  an  equilibrium,  through  which  the  growth 
of  the  former  was  held  in  check  by  the  latter.  On  the  weaken- 
ing of  the  connective  tissue  in  old  age,  the  epithelium  is  allowed 
to  proliferate,  and  tumors  are  formed.  Cohnheim  attached 
great  importance  to  displacement  of  cells  or  groups  of  cells 
from  their  normal  relations  during  the  course  of  development. 
The  idea  of  the  dislocation  of  cells  was  utilized  by  Ribbert  in 
the  explanation  of  the  origin  of  tumors.  He,  however,  con- 
sidered other  forms  of  tissue  dislocation  than  that  which  is 
represented  in  the  so-called  embryonic  rests  of  Cohnheim.  He 
found  that  epithelial  tissue  artificially  implanted  in  the  connec- 
tive tissue  remained  alive  for  a  time  and  was  capable  of  a  certain 
amount  of  growth.  Epithelial  cysts  were  thus  formed,  but 
tissue  transplanted  in  this  way  possessed  only  limited  powers  of 
growth,  and  never  resulted  in  a  tumor.  Ribbert  also  took  into 
account  the  loss  of  the  normal  relations  of  tissues  in  chronic 
inflammations. 

The  theory  of  the  gametoid  nature  of  cancer  tissue  has 
reached  its  greatest  development  with  Farmer,  Moore  and 
Walker,  although  it  is  not  original  with  them .  They  found  that 
in  very  early  cancers  the  epithelial  cells  were  penetrated  by 
leucocytes,  and  from  the  fusion  of  these  cells  of  different  types 
a  hybrid  tissue  resulted  which  possessed  the  properties  of  tumor 
tissue.  Further  support  was  found  for  this  theory  in  the  pres- 
ence in  cancer  cells  of  what  they  considered  to  be  ''  hetero- 
typical  "  and  "  homotypical  "  forms  of  mitosis,  which  had  been 
previously  found  only  in  reproductive  tissue.  In  mitotic 
figures  of  this  sort  not  only  are  the  number  of  chromosomes 
reduced,  but  the  form  assumed  by  the  chromosomes  is  regarded 
as  peculiar  to  sex  cells. 

Von  Hansemann  explains  the  reduction  of  the  number  of 
chromosomes  by  means  of  the  intervention  of  asymmetrical 
mitotic  division.  The  possibility  is  suggested  that  accompany- 
ing the  loss  of  chromatin  there  may  be  also  a  loss  of  differentia- 


8  TYZZER. 

tion,  which  he  terms  "  anaplasia,"  Hansemann  does  not 
mamtain  that  anaplasia  of  itself  results  in  tumor  growth.  A 
stimulus  is  required.  He  considers  it  possible  that  a  stimulus 
which  would  produce  hyperplasia  in  a  normal  tissue  would 
produce  a  tumor  when  acting  on  anaplastic  tissue.  In  this 
connection,  the  changes  found  in  the  chronic  pancreatitis  in 
cats,  a  study  of  which  has  been  made  in  this  laboratory  by  Dr. 
Ordway,  are  well  worthy  of  attention.  The  gland  cells  in  certain 
areas  are  devoid  of  zymogen  granules,  are  of  small  size,  and  are 
faintly  stained.  Mitotic  figures  are  frequently  seen,  and  the 
activity  of  this  epithelium  is  evidently  formative  rather  than 
functional.  It  would  be  of  interest  to  determine  if  this  ana- 
plasia of  the  gland  cells  is  here  the  result  of  asymmetrical 
mitotic  division.  This  sort  of  gland  epithelium  is  so  atypical 
in  its  arrangement  that  structures  are  produced  closely 
resembling  tumor  nodules. 

Certain  principles  concerning  the  regulation  of  the  vegetative 
and  the  propagative  activities  in  cells  have  been  discovered  by 
Hertwig  and  his  pupils,  but  these  will  be  discussed  by  Dr. 
Howard  in  another  lecture. 

Various  facts  which  have  been  brought  forward  tend  to  show 
the  inadequacy  of  the  theories  offered.  It  is  obvious  that 
hypotheses  used  to  bridge  over  the  wide  gaps  where  the  facts 
have  not  been  ascertained  add  nothing  of  themselves  to  the 
knowledge  of  the  subject.  The  successful  transplantation  of 
epithelial  tumors  into  normal  animals  of  the  same  species  would 
indicate  that  a  weakening  on  the  part  of  the  connective  tissue, 
as  suggested  by  Thiersch,  is  not  necessary  for  the  growth  of 
tumor  epithelium.  In  fact,  the  inoculation  of  tumors  is  most 
successful  in  young  animals  in  which  the  connective  tissue 
reaction  is  greatest.  With  Cohnheim's  theory  of  embryonic 
rests  it  is  necessary  to  assume  the  presence  of  cells  throughout 
the  entire  body  which  have  been  arrested  in  the  process  of 
differentiation.  This,  however,  does  not  explain  how  these 
cells  are  stimulated  to  activity,  nor  their  properties  of  unlimited 
growth.  The  theory  of  the  dislocation  of  tissues,  as  advanced 
by  Ribbert  to  account  for  the  origin  of  tumors,  finds  no  support 
in  the  experimental  transplantation  of  normal  tissue,  since  a 
true  tumor  has  never  been  produced  in  the  numerous  experi- 
ments of  this  sort,  although  fetal  as  well  as  adult  tissues  have ' 


TYZZER.  i) 

been  used.  That  certain  tumors  grow  continuously  on  trans- 
plantation demonstrates  a  biological  difference  between  tumor 
cells  and  the  cells  of  normal  tissues. 

Apart  from  the  above-mentioned  theories,  there  are  certain 
facts  bearing  on  the  etiology  of  malignant  tumors  which  are 
coming  to  be  well  established.  The  part  played  by  injuries 
and  chronic  inflammation,  although  repeatedly  noted  in  clinical 
observation,  has  been  reluctantly  accepted  by  many  patholo- 
gists. The  frequency  of  the  development  of  carcinoma  subse- 
quent to  x-ray  burns  can  no  longer  be  ascribed  to  simple  coin- 
cidence. The  frequency  of  the  development  of  sarcomata  after 
mechanical  injury  is  now  becoming  recognized.  The  develop- 
ment of  carcinomata  is  apparently  oftener  associated  with  in- 
flammatory changes  of  considerable  duration.  The  number 
of  special  forms  of  cancer  is  continually  growing.  Bashford, 
besides  mentioning  the  paraffin,  petroleum,  arsenic  and  aniline 
workers'  cancers,  the  smoker's  cancer  and  the  brain  cancers  of 
cattle,  also  describes  certain  cancers  occurring  in  unusual 
situations  and  associated  with  peculiar  forms  of  irritation.  The 
so-called  Kangri  cancer  frequently  develops  upon  the  abdomi- 
nal wall  of  the  natives  of  Kashmir,  India,  where  the  cus- 
tom prevails  of  maintaining  body  warmth  by  means  of  the 
Kangri,  a  small  earthenware  stove  worn  suspended  against  the 
abdomen. 

The  "  horn  core  "  cancer  of  cattle  occurs  where  draft  animals 
draw  their  load  by  a  line  attached  to  the  right  horn.  Tumors 
are  not  infrequently  associated  with  parasites.  Borrel,  Bash- 
ford  and  I  have  found  worms  in  association  with  tumors  in  mice. 
Cancer  of  the  bladder  is  frequent  in  Bilharzia  disease,  and 
cancer  not  infrequently  originates  in  old  lupus  scars.  Attention 
has  been  called  by  numerous  investigators  to  the  endemic 
occurrence  of  tumors  in  the  lower  animals.  Whether  the 
prevalence  of  tumors  among  animals  kept  in  certain  localities 
or  under  peculiar  conditions  is  due  to  the  environment  in  which 
they  are  kept  or  to  certain  inherited  tendencies  is  not  fully 
proven.  The  frequency  of  the  occurrence  of  tumors  in  such 
cases  scarcely  warrants  the  interpretation  of  cancer  as  an  infec- 
tious disease.  It  is  not  improbable,  however,  that  parasites, 
or  even  true  infections,  may  have  an  indirect  influence  in  the 
origin  of  tumors. 


10  TYZZER. 

The  work  of  Loeb  on  the  experimental  production  of  decidual 
tissue  has  an  important  bearing  on  the  origin  of  tumors.  He 
found  that  by  injuring  the  endometrium  of  certain  animals, 
either  within  a  given  period  after  copulation  or  within  a  similar 
period  after  the  phenomenon  of  heat  unattended  by  copulation, 
an  indefinite  number  of  nodules  of  decidual  tissue  could  be 
produced.  Growth  in  this  tissue  was  always  simultaneous 
with  the  development  of  corpora  lutea,  and  if  the  latter  were 
destroyed  the  decidual  tissue  then  failed  to  develop. 

He  concludes  that  the  corpora  lutea  manufacture  a  substance 
which  prepares  the  connective  tissue  cells  of  the  endometrium 
for  active  growth  when  stimulated  later,  either  by  the  presence 
of  the  ovum  or  by  mechanical  injury.  That  this  ^'  preparatory 
substance  "  of  itself  does  not  produce  proliferation  is  seen  by 
the  fact  that  not  all  the  endometrium  in  these  animals  is  en- 
gaged in  the  development  of  decidual  tissue.  That  it  affects 
only  the  connective  tissue  of  the  endometrium  and  not  the 
connective  tissue  of  the  body  in  general  may  be  due  either  to 
the  peculiar  character  of  the  former  or  to  its  association  with 
uterine  glands. 

It  thus  seems  to  be  well  established  that  irritations  of  diverse 
sorts  play  an  important  part  in  the  origin  of  malignant  tumors, 
but  the  problem  of  etiology  will  not  be  cleared  until  it  is 
shown  how  these  conditions  excite  the  tissues  to  unlimited 
growth. 

Concerning  the  diagnosis  of  tumors,  much  has  been  done  with 
the  end  in  view  of  elaborating  tests  by  which  the  presence  of 
internal  tumors  could  be  ascertained.  It  is  well  recognized 
that  there  are  no  specific  symptoms  by  which  tumors  may  be 
diagnosed.  In  fact,  tumors  are  often  far  advanced  in  their 
development  before  any  disturbance  of  function  is  noted.  With 
certain  of  the  experimentally  inoculable  tumors  it  has  been 
found  that  the  serum  of  the  animal  in  which  the  tumor  is 
growing  possessed  hemolytic  properties  for  the  red  blood  cor- 
puscles of  normal  individuals.  The  corpuscles  of  the  tumor 
animal  are  not  hemolyzed.  Crile  has  applied  this  principle 
in  an  attempt  to  obtain  a  diagnostic  test  for  the  presence  of 
tumors.  He  found  that  the  serum  of  persons  possessing  early 
malignant  growths  showed  marked  hemolytic  properties^ 
whereas  the  serum  of  persons  with  benign  growths  did  not. 


TYZZER.  11 

The  serum  from  cases  of  advanced  malignant  growths  failed  to 
produce  hemolysis.  The  reliability  of  this  test  has  not  been 
definitely  established,  although  it  is  not  denied  that  the  sera  of 
many  cancer  cases  possess  hemolytic  properties.  Difficulty 
is  found  in  the  fact  that  the  serum  in  other  conditions,  notably 
tertiary  syphilis,  has  been  found  to  be  also  hemolytic. 

For  the  present,  therefore,  diagnosis  is  usually  established 
by  the  histological  examination  of  excised  tissue.  Even  here 
difficulties  arise.  Although  in  most  cases  tumors  are  suffi- 
ciently advanced  as  to  make  their  recognition  possible,  in  certain 
instances  it  is  impossible  to  decide  whether  or  not  we  deal  with 
a  tumor.  There  must  be,  theoretically  at  least,  all  transitions 
between  the  normal  tissues  and  tumors.  Furthermore,  when 
dealing  with  recognized  tumors  it  is  difficult  to  decide  whether 
we  are  dealing  with  benign  or  malignant  tumors.  The  nature 
of  the  tissue,  the  relative  proportion  of  cells  to  intercellular 
substance,  the  evidence  of  invasion  of  normal  tissue  and  the 
rate  of  growth  as  shown  by  the  frequency  of  mitotic  figures  are 
all  taken  into  account.  The  distinction  between  benign  and 
malignant  growths,  however,  remains  an  arbitrary  one,  and  the 
possibility  of  accurately  prophesying  the  future  biological 
behavior  of  an  apparently  benign  tumor  must  be  questioned. 

The  subject  of  treatment  will  be  considered  in  other  lectures 
of  this  course,  so  that  I  will  say  nothing  more  than  that  the 
experimental  investigation  of  tumors  has  shown  no  mode  of 
treatment  which  compares  with  complete  surgical  extirpation 
of  tumors. 

Such  are  some  of  the  general  problems  of  cancer.  If  we  turn 
now  to  the  trend  of  recent  tumor  investigation,  it  will  be  found 
that  there  has  been  great  activity  in  the  investigation  of  experi- 
mentally inoculable  tumors.  The  study  of  the  natural  incidence 
of  tumors  in  different  species  of  animals  has  shown  their  wide 
distribution  throughout  the  vertebrate  series.  Types  of  tumors 
are  found  which  are  more  or  less  peculiar  to  certain  given  species, 
and  tumors  appear  to  be  more  frequent  in  some  species  than  in 
others.  Notwithstanding  the  type  peculiarities  presented  by 
each  species,  there  is  perfect  analogy  between  the  tumors  of 
animals  and  of  man.  Since  in  animals  we  may  to  a  large  extent 
control  conditions,  opportunity  is  afforded  for  the  most  promis- 
ing line  of  investigation.     As  more  study  is  devoted  to  the 


12  TYZZER. 

tumors  of  any  given  species,  the  types  of  tumors  described  are 
constantly  increasing  in  number.  Discrepancies  in  the  results 
obtained  by  different  investigators  in  this  field  are  usually  due 
to  differences  in  the  methods  employed.  Apolant  states  that, 
of  the  tumors  in  mice,  95%  are  external  tumors  of  mammary 
origin.  I  have  now  studied  a  series  of  62  primary  tumors  in 
mice,  and  of  these,  37,  or  about  60%,  originated  in  the  lung. 
The  next  most  frequent  type  of  tumor  in  my  series  is  the  lympho- 
sarcoma, of  which  there  were  10.  Only  8  of  the  62  tumors  were 
situated  externally,  and  of  these,  6  were  epithelial  tumors. 
There  were  4  tumors  of  the  kidney,  2  of  which  are  undoubted 
hypernephroma.  There  were  ovarian  tumors  in  2,  and  a  sar- 
coma in  1. 

Different  types  of  tumors  frequently  occur  in  a  single  animal. 
Of  the  49  animals  of  this  series,  11  presented  primary  tumors 
of  two  types,  and  1,  primary  tumors  of  four  types.  In  the 
latter  there  was  a  hypernephroma,  a  lymphosarcoma,  a  papil- 
lary cystadenoma  of  the  lung  and  an  adenocarcinoma  of  the 
ovary.  About  25%  of  these  cases,  therefore,  presented  mul- 
tiple tumors  of  different  types.  Multiple  primary  tumors  were 
probably  present  in  a  far  greater  proportion,  for  in  many  cases 
the  lung  tumors  were  multiple  and  occurred  not  only  in  single 
but  in  several  lobes. 

Many  of  the  tumors  which  develop  spontaneously  in  mice 
and  rats  have  been  found  to  be  inoculable.  The  careful  histo- 
logical study  of  a  series  of  the  inoculated  tumors  taken  at  short 
periods  after  their  injection  has  shown  conclusively  that  the 
development  of  the  tumors  depends  upon  the  transplantation 
of  tumor  cells.  The  injected  tissue  is  at  first  surrounded  by  an 
exudate  which  results  from  the  injury  caused  by  the  injection. 
The  tumor  cells  continue  to  grow,  and  mitotic  figures  are  found 
at  all  stages.  There  is  usually,  however,  a  tendency  on  the  part 
of  the  central  portion  of  the  implanted  mass  to  undergo  necrosis. 
This  necrosis  is  progressive  until  the  tumor  tissue  comes  to  be 
in  actual  contact  with  the  connective  tissue  of  the  host,  and  has 
begun  to  be  vascularized.  The  stroma  of  inoculated  epithelial 
tumors  apparently  undergoes  necrosis  and  a  new  stroma  is  fur- 
nished by  the  connective  tissue  of  the  host.  The  reaction  of  the 
connective  tissue  and  the  blood  vessels  to  the  injected  tumor 
tissue  varies  with  different  strains  of  tumors.     From  this  study 


TYZZER.  13 

it  is  obvious  that  production  of  tumors  by  the  experimental 
inoculation  of  tumor  tissue  is  brought  about  by  the  transplanta- 
tion of  cells  rather  than  by  the  introduction  of  a  virus.  The 
tumors,  therefore,  do  not  develop  from  the  tissues  of  the  inocu- 
lated animal,  but  from  the  transplanted  tumor  cells. 

In  a  former  publication^  I  called  attention  to  the  frequency 
of  tumors  in  certain  families  of  mice.  In  one  family  of  25  mice 
there  were  4  primary  adenocystomata  of  the  lung.  Another 
family  was  derived  by  the  breeding  together  of  the  offspring  of 
a  female  mouse  .with  a  large  adenocystoma  of  the  lung.  After 
100  mice  were  obtained,  the  breeding  was  stopped,  and  the  mice 
were  then  kept  under  observation.  Of  this  family  of  100  mice, 
89  are  now  dead.  Definite  tumors  were  found  in  15  of  these. 
Practically  1  mouse  in  6  developed  a  tumor.  A  considerable 
number  of  these  mice  died  while  young  of  infectious  diseases, 
accidental  conditions,  etc.  Inasmuch  as  in  the  above  estimate 
all  were  counted  irrespective  of  the  age  attained,  the  proportion 
of  those  developing  tumors  is  large.  Thirteen  of  these  mice 
presented  adenocystomata  of  the  lung  similar  to  that  which 
was  found  in  the  mother  of  the  family,  2  had  mammary 
tumors  in  addition  to  lung  tumors,  and  1  had  double  ovarian 
tumors. 

Although  the  relation  of  heredity  to  tumors  is  studied  much 
more  readily  in  short-lived  animals  than  in  man,  it  is  attended 
with  difficulties,  especially  in  the  way  of  providing  controls. 
In  this  instance  another  family  of  mice,  which  had  never  devel- 
oped a  tumor,  was  taken  for  comparison  with  the  one  just  men- 
tioned. A  tumor  of  the  lung  was  finally  found  in  a  member 
of  the  supposedly  insusceptible  family.  It  would  be  necessary, 
therefore,  to  show  a  constant  and  frequent  occurrence  of  tumors 
in  a  given  family  to  establish  the  existence  of  an  inherited 
tendency. 

Another  phase  of  the  study  of  inheritance  was  taken  up, 
employing  an  inoculable  tumor.  There  are  numerous  observa- 
tions on  racial  differences  of  susceptibility  to  the  inoculable 
tumors.  The  attempt  has  not  to  my  knowledge  been  made 
of  carrying  out  systematic  breeding  experiments  for  the  deter- 
mination of  the  part  played  by  heredity.  The  tumor  used  in 
this  case  originated  in  a  Japanese  waltzing  mouse,  and  proved 

1  Fourth  report  of  the  Cancer  Commission  of  Harvard  University,  1907 


14  TYZZER. 

to  be  peculiarly  adapted  for  this  sort  of  experimentation.  From 
the  first  it  grew  in  practically  100%  of  all  waltzing  mice  inocu- 
lated. Its  rate  of  gro\\i:h  was  slow,  but  fairly  uniform,  and 
tumors  which  attained  large  size  showed  but  little  necrosis,  so 
that  inoculations  were  attended  with  uniform  results. 

The  attempt  was  made  to  inoculate  common,  tame  mice 
with  this  tumor  with  negative  result.  The  idea  then  suggested 
itself  of  obtaining  hybrids  and  determining  if  they  were  suscep- 
tible. Hybrids  were  obtained  by  breeding  together  common 
males  and  Japanese  waltzing  female  mice.  Such  hybrids  were 
found  to  be  susceptible,  and  the  tumors  grew  more  rapidly  in 
them  than  in  the  control  waltzing  mice.  Hybrids  were  ob- 
tained from  Japanese  waltzing  males  and  common  females. 
These  were  also  susceptible.  These  results  suggested  that  the 
susceptibility  to  the  inoculable  tumor  might  be  of  the  nature  of 
a  Mendelian  character,  which  would  then  necessarily  be  domi- 
nant since  it  was  apparent  in  the  first  generation  of  offspring. 
The  Mendehan  expectanc}^  would  be,  therefore,  that  in  the  next 
generation  25%  of  the  mice  would  be  insusceptible. 

Fifty-four  mice  of  the  second  generation  of  hybrids  were 
inoculated,  with  negative  result  in  every  case.  In  two  or  three 
of  this  number  the  tumor  tissue  evidently  grew  for  a  time,  but 
later  became  rapidly  absorbed  in  every  case.  These  results 
indicate  clearly  that  the  susceptibility  to  this  inoculable  tumor 
is  not  to  be  considered  an  inherited  character  of  the  Mendelian 
sort. 

Sixteen  mice  of  the  third  generation  of  hybrids  were  inocu- 
lated in  order  to  determine  if  the  susceptibility  might  reappear. 
These  proved,  however,  also  insusceptible. 

From  these  data  it  is  evident  that  heredity  is  of  considerable 
importance  in  the  interpretation  of  results  in  the  investigation 
of  the  inoculable  tumors.  Its  influence  is  seen  in  the  great 
susceptibiht}^  of  Japanese  waltzing  mice,  and  in  the  absolute 
insusceptibility  of  common  mice.  There  is,  however,  no  evi- 
dence of  Mendelian  inheritance  of  susceptibility  or  insuscep- 
tibihty,  so  that  the  influence  of  heredity  remains  obscure. 
These  results  are  of  biological  interest  in  that  the  tumor  grows 
in  certain  varieties  of  mice  and  fails  to  grow  in  others,  although 
the  different  varieties  breed  freely  with  each  other. 

In  order  to  determine  the  nature  of  the  insusceptibility  of  the 


TYZZER.  15 

second  and  third  generations  of  hybrids,  a  histological  study  is 
now  being  made  of  the  subject.  The  tumor  has  been  taken  at 
different  intervals  of  time  after  its  inoculation  into  comparative 
series  of  susceptible  and  insusceptible  mice.  Japanese  waltzing 
mice  were  used  for  susceptible  and  second-generation  hybrids 
for  insusceptible  stock.  The  reaction  of  the  host  tissue  to  the 
inoculated  tumor  was  practically  identical  in  susceptible  and 
insusceptible  mice  up  to  the  seventh  day.  The  tumor  epithe- 
lium had  acquired  a  stroma  and  had  become  largely  vascularized 
in  the  insusceptible  as  well  as  in  the  susceptible  mice.  The 
next  preparations  taken  at  ten  days,  however,  showed  a  com- 
plete and  apparently  sudden  necrosis  of  the  tumor  epithelium, 
while  in  the  susceptible  mouse  there  was  a  well-established 
tumor.  This  result  indicates  the  development  of  an  immunity 
subsequent  to  the  inoculation. 

Curative  properties  have  been  claimed  for  the  serum  of  mice 
refractory  to  tumor  inoculation.  Large  doses  of  clefibrinated 
blood  of  previously  inoculated  insusceptible  hybrid  mice  were 
inoculated  into  mice  with  tumors .  In  the  small  number  of  cases 
done  no  curative  action  was  observed. 

In  testing  the  susceptibility  of  the  various  series  of  mice, 
observations  have  been  made  concemiiig  the  effect  of  the  growth 
of  the  tumor  on  the  rest  of  the  body.  In  a  series  of  mice  which 
developed  tumors  of  great  size  there  was  distinct  hypertrophy 
of  the  heart,  and  the  weight  of  the  body  apart  from  the  tumor 
was  increased  as  compared  with  controls.  The  liver  was  in 
some  instances  several  times  the  weight  of  the  normal,  but  this 
was  probably  in  part  due  to  congestion  through  failure  of  com- 
pensation. The  kidneys  and  spleen  were  also  increased  in 
weight.  The  enlargement  of  the  spleen,  however,  probably 
resulted  from  the  absorption  of  toxic  substances  from  the 
necrotic  portion  of  the  tumor.  It  seems  that  this  increase  in 
the  weight  of  the  organs  represents  a  hj'pertrophy  brought 
about  by  the  extra  weight  and  possibly  the  nutritional  demands 
of  the  tumor. 

An  attempt  was  made  to  find  some  relation  between  the  rate 
of  body  gro-^th  and  tumor  growth.  It  was  foimd,  however, 
that  there  was  no  constant  correlation.  In  some  instances  the 
most  rapidly  growing  animals,  while  in  others  the  slowly  grow- 
ing animals,  produced  the  largest  tumors.     In  their  ultimate 


16  TYZZER. 

development,  tumors  attain  greater  size  in  large  than  in  small 
animals.  It  seems  probable  that  the  nutrition  of  the  body  is 
sufficient  for  a  time  for  the  needs  of  the  tumor  as  well  as  for 
the  developing  tissues.  It  appears  that  in  some  instances  the 
demands  of  the  tumor  tissue  are  greater  than  those  of  the  nor- 
mal tissues.  In  one  instance  five  young  mice  which  had  been 
inoculated  all  presented  tumors. 

One  mouse,  which  was  rather  smaller  than  the  others,  lost 
weight  and  finally  became  emaciated.  The  tumor  developed 
in  this  mouse,  but  was  much  smaller  than  in  any  of  the  others. 
It  was  found  that  this  mouse  had  been  gradually  starved 
through  a  deformity  of  the  teeth,  preventing  its  eating.  The 
rate  of  tumor  growth  had  been  diminished  by  the  starvation, 
but  it  nevertheless  grew  to  a  certain  extent  at  the  expense  of  the 
rest  of  the  body. 

The  pessimism  sometimes  expressed  concerning  the  cancer 
problem  serves  only  to  discourage  investigation.  It  is  evidently 
based  in  many  instances  on  the  assumption  that  all  tumors  arise 
from  congenital  defects  or  abnormalities.  The  successive 
description  and  exploitation  of  a  long  list  of  pseudo-parasites 
have  served  to  bring  discredit  to  this  field  of  investigation,  and  the 
inadequacy  of  various  theories  advanced  concerning  the  origin 
of  tumors  has  served  to  strengthen  the  doubt.  It  is  sometimes 
stated  that  there  is  no  advance  in  our  knowledge  of  tumors.  In 
addition  to  the  establishment  by  clinical  observation  of  the  part 
played  by  chronic  inflammation,  the  experimental  investiga- 
tion of  tumors  has  yielded  certain  definite  results,  which  show 
such  statements  to  be  erroneous. 

First  it  is  proven  by  transplantation  experiments  that  cancer 
cells  differ  biologically  by  their  property  of  unlimited  growth 
from  normal  tissue  cells. 

Peculiar  conditions  are  not  essential  for  the  continuation  of 
this  growth.  Certain  tumors  grow  in  normal  individuals. 
Other  tumors,  however,  require  a  special  soil;  they  grow  if 
transplanted  into  other  parts  of  the  same  individual,  but  not  if 
transplanted  to  other  individuals. 

Growth  is  found  to  depend  upon  the  biological  character  of 
the  cells  and  not  upon  their  dislocation. 

The  experimental  investigations  have  made  untenable  the 
interpretation  of  cancer  as  an  infectious  disease. 


TYZZER.  17 

The  development  of  sarcoma  in  animals  inoculated  with 
epithelial  tumors  is  interpreted  by  most  investigators  with 
whom  it  has  occurred  to  be  the  result  of  the  irritating  influence 
of  the  tumor  epithelium. 

The  demonstration  of  the  presence  of  substances  which  pre- 
pare tissue  for  growth  on  subsequent  injury  or  stimulation  is  of 
great  importance. 

There  is,  therefore,  no  more  basis  for  pessimism  with  regard 
to  the  tumor  problem  than  there  was  formerly  for  a  similar 
attitude  with  respect  to  the  problem  of  the  infectious  diseases. 
The  latter  remained  unsolved  until  the  advent  of  the  experi- 
mental method  of  research.  The  experimental  investigation 
of  tumors  has  been  but  recently  taken  up,  and  it  has  already 
yielded  valuable  results.  The  problems  of  growth  are  of  broad 
biological  significance,  and  they  should  not  be  considered  solely 
from  the  point  of  view  of  medicine.  Up  to  the  present  time  no 
more  is  known  of  the  principles  regulating  normal  growth  than 
is  known  of  those  principles  concerned  in  the  abnormal  growth 
of  tumor  tissue.  It  is  possible  that  the  investigation  of  one 
may  eventually  throw  light  on  the  other.  The  essential  prob- 
lem is,  therefore,  one  of  growth,  and  its  investigation  concerns 
the  biologist,  the  zoologist  and  the  embryologist,  as  well  as  the 
physician. 


The  Histological  Classification  of  Tumors.*! 

BY  F.  B.  MALLORY,  M.D., 

BOSTON,    MASS., 
Associate  Professor  of  Pathology,  Harvard  Medical  School. 

Normal  cells  and  tissues  are  classified  according  to  striking 
morphological  characters  which  distinguish  different  kinds  of 
cells  from  one  another.  These  characters,  aside  from  size  and 
shape  of  cells  and  nucleus,  may  lie  within  the  cell  (eosinophihc 
granules,  axis  cylinder  processes)  or  be  extracellular  substances 
produced  by  the  cells  (collagen  fibrils,  osteoid  substance) .  They 
represent  the  differentiation  which  the  cells  undergo  in  order 
to  perform  their  different  functions. 

Tumor  cells  tend  to  differentiate  hke  normal  cells;  hence 
tumors  are  usually  classified  histologically  like  normal  tissues, 
that  is,  according  to  the  microscopic  structure  of  their  cells  and 
intercellular  substances.  In  tumors  which  grow  slowly,  the 
differentiation  of  the  cells  is  usually  well  marked;  in  those  which 
grow  rapidly,  it  may  be  slight  or  wanting.  It  is  important, 
therefore,  to  study  embryological  as  weU.  as  normal  tissues  so 
as  to  have  a  clear  Icnowledge  of  how  muscle  and  other  cells  look 
in  the  early  stages  of  differentiation.  A  knowledge  of  embrj'- 
ology  is  also  useful  in  explaining  the  location  of  certain  tumors 
(a  glioma  over  the  coccyx)  and  the  nature  of  such  a  tumor  as 
the  chordoma  which  arises  from  remains  of  the  notochord, 
a  fetal  tissue. 

In  classifying  tumors,  it  is  important  to  ascertain  what  is  the 
one  essential  cell  in  each  type  of  simple  tumor  and  to  name  the 
tumor  accordingly,  leaving  out  of  consideration  the  blood 
vessels  and  connective  tissue  of  the  stroma.  They  are  furnished 
by  the  tissues  in  the  midst  of  which  the  tumor  develops  because 
there  is  a  physiological  demand  made  for  them  by  the  tumor 
cells.     All  tumors  composed  of  one  type  of  cell,  at  whatever 

*  A  lecture  under  the  auspices  of  the  Cancer  Commission  of  Harvard  University, 
t  Synopsis  of  lecture,  which  was  illustrated  by  one  hundred  and  twenty-seven  lantern 
slides. 

19 


20  MALLORY. 

rate  of  speed  they  are  multiplying,  should  be  considered  under 
one  heading,  not  separated  into  slowly  and  rapidly  growing 
groups  and  described  separately.  Such  a  separation  is  artificial 
and  misleading. 

The  essentials  for  the  exact  diagnosis  of  tumors,  especially 
those  which  are  growing  rapidly,  are  perfectly  fresh  tissues 
obtained  at  the  operating  table  if  possible,  immediate  fixation 
in  proper  solutions  which  will  preserve  faithfully  all  the  morpho- 
logical characters  on  which  an  exact  diagnosis  depends,  and 
special  staining  methods  to  render  prominent  the  characteristic 
structures, 

A  limited  number  of  characteristic  cells  will  be  described  and 
some  varieties  of  tumors  composed  of  them  will  be  demonstrated 
photomicrographically. 

The  ordinary  connective  tissue  cell  or  fibroblast  is  an  elon- 
gated, flattened  cell  with  a  flat,  oval  nucleus.  It  is  character- 
ized by  the  production  of  two  kinds  of  fibrils  (fibrogiia  and 
collagen  fibrils)  which  can  be  stained  in  sharp  contrast  to  each 
other.  The  fibrogiia  fibrils  are  in  intimate  contact  with  the 
cytoplasm  of  the  cell;  the  collagen  fibrils  are  entirely  free  from 
it;  they  both  run  parallel  with  the  long  axis  of  the  cell.  Cells 
of  this  type  produce  a  series  of  tumors  ranging  from  the  dense 
fibroma  to  the  soft  rapidly  growing  fibrosarcoma  (so-called 
spindle-cell  sarcoma).  Even  in  the  most  rapidly  growing 
tumors  of  this  series  both  kinds  of  fibrils  are  produced,  although 
they  may  be  very  delicate  and  few  in  number.  Occasionally 
some  of  the  cells  contain  multiple  mitoses  and  others  large 
lobulated  or  multiple  nuclei  with  numerous  centrosomes. 

The  myxoma  andm  yxosarcoma  differ  from  the  tumors  of  this 
group  only  in  having  a  certain  amount  of  fluid,  containing  more 
or  less  mucin,  between  the  collagen  fibrils.  They  should  not, 
therefore,  be  classed  as  a  separate  type  of  tumor. 

The  smooth  muscle  cell  is  a  long  spindle-shaped  cell  with  a 
rod-shaped  nucleus.  It  is  characterized  by  a  number  of  fine 
striations  running  longitudinally  in  the  cuticle  of  its  cytoplasm. 
Towards  the  tapering  ends  of  the  cell  these  striations,  termed 
myoglia  fibrils,  coalesce  more  or  less  intimately  to  form  what 
appear  to  be  coarse  fibrils.  Slowly  and  rapidly  growing  tumors 
composed  of  this  type  of  cell  (leiomyomata)  occur  most  com- 
monly in  the  uterus,  but  may  arise  in  other  parts  of  the  body. 


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MALLORY.  21 

In  one  rapidly  growing  malignant  leiomyoma,  in  parts  where 
the  cells  were  proliferating  most  rapidly,  they  ceased  forming 
fibrils  and  became  more  or  less  spherical  in  shape. 

The  neuroglia  cell  varies  considerably  in  shape  and  size.  It 
may  be  round  or  spindle  shaped,  or  of  intermediate  form.  It  is 
characterized  by  the  production  of  fibrils  of  one  kind  only,  the 
neurogha  fibrils,  which  run  parallel  with  the  spindle-shaped  cell 
and  in  all  directions  around  the  spherical  cells.  These  fibrils 
touch  the  cytoplasm  of  the  cell  to  which  they  belong  in  some 
part  of  their  course.  From  this  type  of  cell  quite  a  variety  of 
gliomata  arise,  some  of  which  grow  slowly,  while  others  multiply 
rapidly  and  may  invade  the  pia  of  brain  or  cord  and  grow  along 
it.  One  glioma  occurring  over  the  coccyx  and  giving  rise  to 
metastases,  in  both  groins  evidently  arose  from  remains  of  the 
neural  canal. 

The  endothelial  cell  is  characterized  by  no  production  of 
fibrils;  hence.it  stands  out  in  marked  contrast  to  the  cells  already 
described.  It  gives  rise  to  two  types  of  tumors,  the  hemangio- 
endothelioma and  the  lymphangio-endothelioma.  The  first 
type  occurs  in  two  varieties,  the  capillary  and  the  cavernous. 

The  capillary  hemangio-enclothelioma  occur  in  the  form  of 
small  blood  vessels  which  invade  fat,  muscle  and  nerve  tissues, 
and  occasionally  grow  within  veins  and  arteries.  The  endo- 
thelial cells  sometimes  form  several  layers  around  the  lumina 
of  the  vessels,  giving  the  appearance  of  a  perithelial  growth,  and 
rarely  papillary  masses  of  endothelial  cells  may  project  into  the 
lumen  of  a  vessel  and  more  or  less  occlude  it.  If  through 
rupture  or  pressure  the  lumina  of  the  vessels  become  obliterated, 
the  endothelial  cells  grow  in  masses  and  whorls.  After  a  time 
collagen  fibrils  extend  in  between  the  endothelial  cells  from  the 
connective  tissue  cells  of  the  stroma  and  transform  the  tumor 
into  what  looks  like  a  fibrosarcoma,  but  fibroglia  fibrils  are 
lacking. 

In  four  cases  of  gradually  extending  cavernous  hemangio- 
endothelioma the  tumors  were  found  to  consist  of  endothelial 
cells,  supported  by  thin  layers  of  connective  cells  and  fibrils, 
growing  within  and  along  blood  vessels.  In  places  they  distend 
or  burst  through  the  vessel  walls  so  as  to  form  tumor  nodules 
composed  of  large  blood  spaces  separated  by  thin  septa  of 
•connective  tissue  covered  on  both  sides  with  endothelial  cells. 


22  MALLORY. 

A  neuroma  of  adrenal  origin,  with  widely  distributed  metas- 
tases, was  characterized  by  masses  of  delicate  fibrils  whicK 
reacted  to  a  variety  of  stains  like  nerve  fibrils. 

The  neuromata  of  the  eye  have  been  shown  by  Verhoeff  to 
consist  of  nerve  cells  which  tend  to  differentiate  like  the  cells  of 
the  retina.  The  rosettes  occurring  in  these  tumors  often  show 
very  definite  rods  and  cones  projecting  through  an  external 
limiting  membrane  just  as  the  normal  rods  and  cones  do. 

In  the  rhabdomyoma  the  cells  tend,  by  differentiation  of  the 
cytoplasm,  to  produce  the  sarcous  elements  of  the  normal  fetal 
striated  muscle  cells. 

In  the  chordoma  occurring  at  the  base  of  the  skull  the  curious 
vacuolated  cells  of  the  notochord  are  faithfully  reproduced. 

Epithelial  cells  occur  in  great  variety;  so,  also,  do  the  epi- 
thelial tumors  of  which  the  cells  tend  to  differentiate  like  the 
normal  cells.  It  is  advisable,  therefore,  to  study  by  themselves 
each  type  of  normal  epithelial  cell  and  the  group  of  tumors  with 
cells  differentiating  like  it.  Only  the  names  of  a  few  can  be 
mentioned  here:  The  adenomata  of  the  mammary  and  coil, 
glands  with  the  layer  of  smooth  muscle  cells  surrounding  the 
epithehal  cells;  the  various  types  of  carcinoma  of  the  breast; 
the  characteristic  benign  and  malignant  epithelial  tumors  of 
adrenal  cell  origin;  the  chorio-epithelioma  derived  from  fetal 
epithelium  covering  the  chorionic  villi;  the  ciliated  epithelial 
tumors  derived  from  remains  of  the  Wolffian  duct,  and  the 
adamantinoma  derived  from  remains  of  the  enamel  organ. 

The  vague  terms  "  spindle  and  round-cell  sarcoma, "  and 
"  perithehal  angiosarcoma  "  should  be  avoided  so  far  as  possible. 
A  spindle-cell  sarcoma  may  be  composed  of  connective  tissue^ 
smooth  muscle,  endothelial  or  neuroglia  cells.  A  round-cell 
sarcoma  may  in  reality  be  a  lymphoma,  osteosarcoma,  malignant, 
leiomyoma  or  neuroma.  A  true  perithelial  angiosarcoma  does 
not  occur.  The  tumors  which  most  frequently  show  such  an 
appearance  are  the  melanotic  sarcoma  and  the  neuroma  of  the 
eye;  rarely  even  a  carcinoma  of  the  breast  may  exhibit  this  type 
of  growth  which  is  purely  nutritional  in  origin.  The  cells  at  a. 
distance  from  the  blood  vessels  undergo  necrosis  and  absorption,, 
leaving  the  vessels  isolated  with  a  sheath  of  tumor  cells  around 
them. 


Some  Aspects  of  the  Pathological  Physiology  of 
Intracranial  Tumors.* 

BY  HARVEY  GUSHING,  M.D., 

BALTIMORE,    MD., 
Associate  Professor  of  Surgery,  Johns  Hopkins  University. 

Intracranial  growths  are  of  peculiar  gravity  to  the  individ- 
ual inasmuch  as  they  affect  the  most  vital  organ  of  his  body. 
To  the  physiologist  and  pathologist  they  are  of  peculiar  interest 
by  reason  of  the  light  they  often  shed  on  the  localization  of 
function  and  the  unusual  physical  disturbances  which  arise  in 
consequence  of  their  origin  within  a  rigid  bony  chamber.  To 
the  clinician  they  are  of  peculiar  importance  owing  to  their 
frequent  occurrence  and  the  ease  with  which  they  may  be  over- 
looked. 

There  seems  to  be  little  basis  for  the  prevalent  belief  that  a 
brain  tumor  is  a  relatively  rare  lesion,  particularly  if  we  are  to 
include  with  "  tumors  "  the  infectious  granulomata,  cysts  and 
the  neoplasms  which  arise  in  the  cerebral  envelopes  and  subse- 
quently crowd  their  way  into  the  cranial  cavity.  Oppenheim 
goes  so  far  as  to  regard  the  brain  as  the  seat  of  predilection  for 
new  growths,  and  Bruns  with  some  severity  affirms  that  when 
a  general  practitioner  says  he  has  never  encountered  an  in- 
stance of  this  disease,  it  is  an  acknowledgment  that  cases  have 
passed  through  his  hands  unrecognized.  Unquestionably  fail- 
ure to  appreciate  the  existence  of  intracranial  growths  in  the 
early  stages  is  among  the  commonest  of  diagnostic  errors. 

Nor  is  it  difficult  to  advance  a  reason  for  this  state  of  things. 
In  reviewing  the  possible  causes  of  a  given  train  of  symptoms 
one  naturally  inclines  toward  the  malady  for  which  the  greatest 
relief  may  be  expected  from  established  methods  of  treatment. 
For  this  reason  syphilis  is  apt  to  be  thought  of  first  in  the  case 
of  brain  tumors.  The  early  recognition  of  any  disease  of  insidi- 
ous onset  is  apt  to  go  hand  in  hand  with  successful  therapeutic 

*  A  lecture  under  the  auspices  of  the  Cancer  Commission  of  Harvard  University, 
Feb;  25,  1909. 

23 


24  GUSHING. 

measures;  if  these  are  vague,  uncertain,  unavailing,  interest 
becomes  lax  and  the  disease  reaches  a  full-blown  stage,  which 
fits  the  textbook  description  considered  typical  of  the  malady, 
before  the  patient  attracts  any  earnest  attention  and  is  induced 
to  enter  the  wards  of  a  general  hospital.  Hence  the  opportunity 
for  observing  any  large  number  of  cases  of  intracranial  tumor 
in  their  incipiency  is  unusual,  and,  owing  to  the  comparative 
infrequency  of  prompt  surgical  exploration  in  the  suspected 
cases,  there  has  been  httle  chance  of  gaining  a  first-hand  knowl- 
edge of  the  early  lesion,  of  acquiring  familiarity  with  the  asso- 
ciated pressure  phenomena  and  of  studying  the  absolutely  fresh 
tissue.  Furthermore,  it  has  been  unusual  likewise  for  these 
unfortunates  to  end  their  days  in  the  wards  of  an  active  hos- 
pital, for  most  of  them  have  a  pitifully  long  history  and  fre- 
quently gravitate  to  asylums  for  the  mentally  afflicted,  where 
an  unsuspected  tumor  is  often  disclosed  at  autopsj^,  as  Black- 
burn's figures  from  the  Government  Hospital  for  the  Insane 
indicate.  But  even  if  the  story  has  terminated  in  a  general 
hospital,  a  post-mortem  view  of  the  terminal  stages  of  tumors 
of  the  brain,  as  of  other  organs,  naturally  gives  the  impression 
of  operative  impossibility,  which  largely  accounts  for  the  hope- 
less outlook  that  statisticians  have  held  in  regard  to  these 
lesions. 

Since  the  opening  of  the  Johns  Hopkins  Hospital,  twenty  years  ago, 
the  pathological  records  show  that,  up  to  Jan.  1,  1909,  in  3,150  autop- 
sies, there  were  55  cases  in  which  brain  tumor  was  found,  —  about 
1.7%,  or  1  case  in  57  autopsies.  This  is  an  even  larger  percentage  than 
that  given  by  Seidel,  who  found,  in  Munich,  an  average  of  1  case  in 
80  autopsies,  or  1.25%;  and  by  v.  Beck,  who  found,  in  Heidelberg, 
an  average  of  1  case  in  120  autopsies,  or  0.8%.  There  are,  of  course, 
many  elements  to  be  considered  in  these  figures,  such  as  the  average 
age  of  hospital  patients,  the  character  of  the  hospital  service,  the 
interest  paid  to  neurological  cases,  etc. 

Bruns  states  that  2%  of  all  patients  classified  as  "  neurological  " 
suffer  from  brain  tumor,  and  Blackburn's  figures  (29  tumors  in  1,642 
autopsies,  nearly  3%)  show  an  equal  percentage  for  all  mentally 
afflicted  (i.  e.,  asylum)  patients. 

In  the  medical  wards  of  the  Johns  Hopkins  Hospital,  in  approxi- 
mately 25,000  admissions  up  to  Jan.  1,  1909,  there  have  been  in  the 
neighborhood  of  20  cases  diagnosed  as  brain  tumor  (?)  in  each  succes- 


GUSHING.  25 

sive  5,000  admissions,  making  an  average  of  1  tumor  case  in  every 
250  patients. 

In  Dr.  Halsted's  surgical  service,  since  the  opening  of  the  hospital 
in  1889,  the  number  of  patients  with  the  diagnosis  of  brain  tumor  has 
risen  from  .06%  in  the  first  5,000  admissions  to  0.2%  in  the  second 
5,000;  to  .3%,  in  the  third  5,000;  to  0.75%  in  the  fourth  5,000;  to 
1.3%  in  the  last  3,000  (i.  e.,  from  Jan.  1,  1907,  to  Jan.  1,  1909).  In 
the  last  1,000  surgical  admissions  there  have  been,  up  to  the  present 
date,  40  brain  tumor  cases,  showing  the  rapid  increase  in  the  per- 
centage of  these  patients  in  a  general  service  to  4  in  every  100 
admissions. 

The  disturbances  occasioned  by  a  tumor  have  been  conven- 
iently divided  into  (1)  general  'pressure  symptoms,  which  in  a 
measure  occur  irrespective  of  the  situation  or  histological  char- 
acter of  the  growth;  and  (2)  focal  or  localizing  symptoms,  which 
are  manifestations  that  indicate  the  area  of  the  brain  implicated. 
For  example,  the  familiar  benign  endothelioma  which  arises 
from  the  meninges  in  the  cerebello-pontine  angle,  in  the  course 
of  its  enlargement  and  encroachment  on  the  intracranial  space, 
will  ultimately  produce  headache,  vertigo  and  paroxysmal  vom- 
iting, together  with  the  well-known  alterations  in  the  eye- 
grounds,  and  at  the  same  time  will  definitely  call  attention  to  its 
situation  by  evidences  of  involvement  of  the  adj  oining  cerebellar 
hemisphere,  as  well  as  by  pressure  palsies  in  the  distribution 
of  the  cerebral  nerves  which  emerge  from  the  pons  in  its  imme- 
diate neighborhood. 

This  commonplace  illustration  of  the  fully  developed  symp- 
tomatology applies  to  the  condition  ultimately  to  be  expected 
in  the  course  of  most  cases  of  tumor  when  the  diagnosis  is 
written  on  the  patient's  retina  if  not  on  his  face.  What  will 
soon  be  demanded  of  us  will  be  the  recognition  of  such  a  lesion 
before  its  symptoms  are  thus  outspoken  —  no  easy  matter,  for 
we  are  cut  off  from  the  more  familiar  methods  of  a  physical 
examination  bequeathed  to  us  by  Auenbrugger  and  Laennec, 
and  only  the  distant  effects  of  a  brain  tumor,  not  the  actual 
lesion,  are  accessible  to  the  eyes,  ears  and  fingers.^ 

^  It  is  true  that  inspection  is  indirectly  aided  by  the  ophthalmoscope  and  occasionally 
by  the  x-ray;  palpation,  by  the  chance  thinning  of  the  bone  overlying  a  growth.  Per- 
cussion, likewise,  is  at  times  useful,  as  Phelps  and  Macewen  have  pointed  out,  and  aus- 
cultation similarly  may  detect  an  aneurismal  bruit.  But  these  are  exceptional  rather 
than  usual  opportunities. 


26  GUSHING. 

I.  THE  GENERAL  EFFECTS  OF  TUMORS. 

In  the  first  place,  a  tumor  may  give  rise  to  pressure  symp- 
toms alone  when  it  occupies  a  "  silent  '^  or  ''  mute  "  area  of  the 
brain,  and  in  consequence  of  our  scant  knowledge  of  the  func- 
tion of  the  larger  part  of  the  cerebrum  the  majority  of  such 
tumors  remain  absolutely  unlocalizable,  even  if  their  presence 
be  suspected.  On  the  other  hand,  a  brain  tumor  early  in  its 
development  may  give  local  symptoms  alone,  with  no  appre- 
ciable pressure  phenomena,  should  it  have  originated  in  a 
''  speaking  "  in  contradistinction  to  a  mute  or  silent  area;  in 
other  words,  when  it  primarily  implicates  centers  or  paths  the 
function  of  which  is  well  understood.  Finally,  a  brain  tumor 
may  be  present  for  years  and  give  rise  to  none  of  the  symptoms 
considered  characteristic  of  a  new  growth,  so  that  a  diagnosis 
of  dementia,  hysteria,  psychoneurosis,  migraine,  headache 
from  eyestrain,  dyspepsia  or  nephritis,  and  what  not,  is  made 
in  the  attempt  to  explain  the  symptomatic  disturbances  which 
may  be  present.  A  tabulation  of  the  various  diagnoses  made 
in  the  early  stages  of  a  series  of  brain  tumor  cases  would  make 
a  professionally  disconcerting  record. 

One  of  Hughlings  Jackson's  characteristic  dicta  reads,  "  The 
study  of  the  thing  caused  must  precede  the  study  of  the  cause 
of  the  thing,"  a  consoling  epigram,  for  with  certain  of  the  symp- 
tomatic pressure  phenomena  of  brain  tumor  we  are  still  in  the 
stage  of  "  studying  the  thing  caused,"  and  this  is  notably  true 
of  the  headache  and  vomiting  —  symptoms  which  do  not 
readily  lend  themselves  to  experimental  methods  of  investiga- 
tion. 

It  is  quite  probable,  in  the  case  of  the  headaches  at  least,  that 
the  "  cause  of  the  thing  "  in  all  instances  is  pressure.  Here, 
however,  we  are  confronted  with  a  problem  very  similar  to  that 
which  has  puzzled  physiologists  and  surgeons  in  the  case  of 
abdominal  pain.  The  organ  itself,  the  brain,  —  like  the  liver, 
the  spleen  and  the  intestines,  —  is  insensitive,  as  is  also  its 
immediately  investing  membrane.  The  cranial  cavity,  how- 
ever, is  lined  with  and  partitioned  by  an  outer  sentient  mem- 
brane, the  dura,  whose  sensory  fibers,  trigeminal  and  vagal,  are 
capable  of  demonstration  by  dissection.  It  has  been  observed 
that    patients,    after   removal    of   the   Gasserian   ganglion   or 


GUSHING.  27 

severance  of  the  trigeminal  nerve,  no  longer  suffer  from  the 
sensation  of  headache  on  the  anesthetic  side  of  the  head.^ 
These  facts  would  favor  the  view  that  the  dura  plays  a  part  at 
least  in  these  subjective  discomforts;  but  it  has  been  found  in  a 
number  of  instances  in  which  cranial  operations  have  been 
performed  without  anesthesia  upon  conscious  patients  that  the 
dura  is  actually  insensitive  to  touch  or  incision,  and  that  a 
sensation  of  pain  is  elicited  only  when  traction  is  made  upon  it. 
This  condition  is  again  comparable  with  that  found  in  the  case 
of  the  abdominal  viscera,  and  Meltzer's  view,  that  it  is  the  mere 
exposure  of  the  viscera  in  an  enfeebled  patient  that  leads  to  their 
apparent  insensitiveness,  is  difficult  to  reconcile  with  what  we 
know  of  other  definitely  sentient  tissues.  It  would  seem,  there- 
fore, that  distortion  of  the  f  alx  or  tentorium  and  the  consequent 
dragging  upon  or  stretching  of  the  membrane  may  be  an  im- 
portant factor.  We  know,  for  example,  that  headaches  are 
often  particularly  agonizing  in  cases  in  which  the  dural  pocket 
enclosing  the  hypophysis  cerebri  is  distended  by  an  enlarge- 
ment of  the  gland,  and  that  they  cease  as  soon  as  the  capsule 
has  been  incised.  It  has  been  learned,  furthermore,  that  the 
headaches  of  tumor  are  often  promptly  and  completely  relieved 
by  a  successful  "  decompressive  "  operation,  and  even  when  a 
certain  amount  of  discomfort  persists  after  these  measures,  its 
severity  varies  with  the  degree  of  tension  evident  in  the  pro- 
truding area.  Indeed,  many  headaches  not  associated  with 
tumor  may  be  of  pressure  origin.  This  is  certainly  true  of  the 
headaches  of  traumatic  edema  and  of  nephritis,  and  may  be  so 
even  of  ordinary  migraine,  judging  from  certain  operative  expe- 
riences which  we  have  met  with  in  these  cases. ^ 

As  the  German  proverb  tells  us,  "  Where  there  is  much  light, 
the  shadow  is  deeper."  And  it  must  be  admitted  that  there 
are  many  points  in  relation  to  headache  not  entirely  explained 
by  assigning  pressure  as  the  cause.  Thus,  a  lumbar  puncture 
with  withdrawal  of  cerebrospinal  fluid  from  a  healthy  individ- 
ual, which  supposedly  brings  about  a  lessening  of  the  normal 
degree  of  tension,  may  occasion  great  intracranial  discomfort, 

^  The  Sensory  Distribution  of  the  Fifth  Cranial  Nerve.  Johns  Hopkins  Hosp.  Bull., 
1904,  vol.  XV,  p.  223. 

2  A  subtemporal  decompression,  performed  in  an  intractable  case  of  this  sort  upon 
a  physician  who  had  suffered  for  years  from  hemicrania,  afiorded  an  unexpected  degree 
of  relief. 


28  GUSHING. 

and  there  are  definite  reflex  headaches  of  gastric  or  ocular  origin, 
and  possibly  those  of  anemia,  which  are  difficult  to  reconcile 
with  this  view.  Moreover,  problems  arise  whose  solution  is 
for  the  psychologist  rather  than  the  physiologist.  Perception 
of  pain  is  unquestionably  a  cerebral  function,  for  without  the 
brain  it  is  inconceivable  that  it  should  exist,  and  yet  the  brain 
itself  (with  the  possible  exception  of  the  basal  ganglia),  so  far 
as  we  know,  is  insensitive  to  the  stimuli  which  give  pain  at  the 
periphery.  Faradization  of  the  supposed  sensory  cortex  in 
two  conscious  patients,  though  giving  vague  tactual  impressions 
referred  to  the  periphery,  was  provocative  of  no  local  sensation 
whatsoever.^ 

Particularly  vague  is  our  knowledge  of  the  agencies  which 
provoke  the  so-called  cerebral  vomiting  —  a  symptom  incon- 
spicuous or  entirely  wanting  in  two  thirds  of  the  cases,  even 
after  they  have  reached  an  advanced  stage  when  other  evidences 
of  pressure  are  pronounced.  Whether  there  is  a  center  for 
this  act  in  the  medulla  —  possibly  vagal  —  can  only  be  con- 
jectured, but  the  symptom  is  thought  to  be  more  common  when 
the  bulb  is  involved.  I  have  seen  a  case  in  which  occasional 
projectile  vomiting  persisted  for  months  after  the  successful 
removal  of  a  frontal  lobe  tumor,  in  spite  of  the  disappearance 
of  all  other  signs  of  pressure. 

In  the  case  of  choked  disk,  however,  our  views  are  clearer,  for  it 
is  an  objective  process  and  lends  itself  readily  to  experimental 
study.  Time  forbids  a  relation  of  the  development  of  our 
knowledge  of  this  interesting  lesion  —  the  most  important  of 
all  symptomatic  evidences  of  intracranical  pressure,  for  the 
discovery  of  which  we  are  indebted  to  Helmholtz  and  his 
"  optical  toy,"  as  he  was  wont  to  call  the  now  invaluable 
ophthalmoscope.  Of  the  many  views  advanced  in  explanation 
of  the  process,  a  number  have  been  based  on  conjecture  alone, 
but  of  the  two  most  important,  one  would  ascribe  the  lesion  to 
purely  mechanical  or  pressure  agencies,  the  other  to  purely 
toxic  or  inflammatory  factors.^ 

1  A  Note  upon  the  Faradization  of  the  Post-Central  Convolutions  of  the  Human 
Brain  in  Conscious  Patients.     Brain,  1909,  vol.  xxxii. 

^  Hence  a  terminology  has  arisen  which  is  confusing.  "  Optic  neuritis  "  or  "  papil- 
litis," introduced  by  Von  Leber  and  signifying  inflammation,  as  opposed  to  "  choked 
disk "  (Clifford  Albutt's  adaptation  of  the  German  term,  "  Stauungsoedema  ")  or 
"  papilledema,"  suggesting  the  swelling  of  vascular  stasis,  are  variously  used  by  different 


GUSHING.  29 

Numerous  observations,  experimental  and  clinical,  have 
served  in  the  past  few  years  to  turn  the  scale  in  favor  of  the 
mechanical  origin  of  the  lesion.  Thus,  a  condition  typical  of  the 
early  stages  of  choked  disk  has  been  found  to  accompany  the 
non-inflammatory  traumatic  edemas  described  by  Cannon  and 
Bullard,  which  so  often  follow  fractures  of  the  skull;  again, 
the  close  affinity  between  the  neuroretinal  lesion  of  tumor  and  of 
nephritis  has  been  demonstrated;  further,  it  has  been  shown 
experimentally  that  a  choked  disk  may  be  produced  by  increas- 
ing the  intracranial  pressure  through  the  introduction  of  fluids 
or  of  a  sterile  elastic  foreign  body  within  the  skull.  But  most 
conclusive  of  all  is  the  rapid  subsidence  of  the  process  which 
often  follows  the  release  from  pressure  brought  about  by  the 
establishment  of  an  adequate  cranial  and  dural  opening. 

After  Schwalbe's  discovery  that  the  investing  sheath  of  the 
optic  nerve  was  merely  a  prolongation  of  the  meninges,  its  com- 
partments communicating  with  the  intracranial  (subdural  and 
subarachnoid)  spaces,  it  became  known,  through  the  experi- 
ments of  Schmidt-Rimpler,  Manz  and  others,  that  an  acute  dis- 
tention of  the  optic  sheath  comparable  to  the  ampullaform  dila- 
tation, well  known  to  pathologists  in  cases  of  brain  tumor,  will 
occur  if  fluid  under  pressure  is  allowed  to  enter  the  intermenin- 
geal  spaces  enveloping  the  encephalon.  These  observations 
have  been  confirmed  by  others  as  well  as  by  workers  in  the 
Hunterian  laboratory,^  where  it  has  been  shown  that  the  dis- 
tention of  the  optic  sheaths,  with  accompanying  congestion  and 
edematous  swelling  of  the  nerve-head, —  a  choked  disk  in  its 
early  stage, —  will  occur  not  only  in  consequence  of  the  intro- 
duction of  fluid  maintained  under  increased  tension,  but  that 
the  fluid  normally  present  in  the  cysternse  about  the  infundibu- 

writers  to  express  the  whole  process  or  to  indicate  its  different  stages.  It  would  seem 
desirable  to  fix  upon  one  term  to  describe  the  lesion  from  its  early  to  its  terminal  stage; 
that  is,  from  the  early  vascular  congestion  of  the  nerve-head  and  retina,  through  the 
stage  of  marked  swelling  of  the  papOla  with  exudates  and  hemorrhage,  to  the  final  stage 
of  new  tissue  formation,  atrophy  and  blindness.  For  this  entire  process,  personally  I 
should  prefer  to  reserve  the  term  "  choked  disk  "  rather  than  to  limit  this  designation 
to  a  stage  of  the  lesion  in  which  there  is  a  certain  measurable  degree  of  swelling.  Marcus 
Gunn  has  suggested  the  term  "  tumor  papillitis,"  which  is  undesirable,  for  the  process 
seems  to  be  the  same  whether  produced  by  the  edema  accompanying  cerebral  injuries,^ 
vascular  disturbances,  nephritis  or  tumor;  and  "  papillitis  "  suggests  inflammation  as 
the  primary  element  —  a  view  that  more  recent  opinion  has  not  supported. 

1  Observations  on  Experimentally  Induced  Choked  Disk.  Johns  Hopkins  Hosp. 
Bull.,  1909,  vol.  XX,  p.  95. 


30  GUSHING. 

lum  may  play  the  same  part  in  case  an  increase  of  intracranial 
pressure  is  similarly  maintained  by  the  introduction  into  the 
cranium  of  bodies  simulating  tumors.  The  fluid  seems  to  pass, 
for  the  most  part,  into  the  subarachnoid  spaces  of  the  optic 
sheath,  though  in  certain  instances  it  may  distend  the  subdural 
space  as  weU.  It  has  not  been  finally  determined  whether  the 
fluid  finds  its  way  from  the  distended  sheath  iato  the  neuro- 
retinal  tissue  by  lymphatic  channels  or  whether  the  swelling 
which  occurs  is  the  result  of  a  stasis  in  the  central  veins  brought 
about  by  the  greater  tension  of  the  fluid  encompassuig  the  nerve. 
Probably  both  elements  play  a  part;  but,  however  this  may  be, 
a  rapid  edema  does  occur,  and  if  by  proper  devices  the  pressure 
can  be  maintained  for  days  or  weeks,  the  edema,  as  elsewhere  in 
the  body  when  accompanied  by  venous  stasis,  is  followed  by 
extravasations  and  infiltration,  which  in  the  course  of  time 
through  the  process  of  new  tissue  formation  will  shut  down  on 
the  nerve  and  lead  to  atrophy  and  blindness.^ 

There  are  other  "  things  caused  "  by  general  pressure  which 
need  no  more  than  mention  in  passing.  Among  these  are 
vertigo  and  dizziness,  convulsions,  the  medullary  symptoms  with 
slowing  of  the  pulse  and  a  transient  rise  in  blood  pressure 
(usually  a  terminal  and  much  less  strikmg  phenomenon  than  in 
the  cases  of  acute  compression  due  to  sudden  vascular  lesions) , 
and  finally, —  what  Dr.  Bordley  and  I  have  come  to  regard  as  an 
early  manifestation  of  tumor, —  the  inversion  or  interlacing  of 
the  color  fields.  This  symptom  has  been  definitely  wanting  in 
only  two  of  a  series  of  forty  cases  in  which  a  careful  perimetric 
examination  was  possible,  and  thus  promises  to  be  a  fairly 
constant  feature  of  pressure  from  tumor,  wherever  its  location, 
and  irrespective  of  the  presence  or  absence  of  an  accompanying 
choked  disk.  This  must  be  regarded  as  an  important  matter 
in  view  of  the  supposed  relation  of  this  phenomenon  to  hysteria. 
Moreover,  this  is  one  of  the  first  symptoms  to  disappear  after 
a  decompression,  so  that  the  normal  relations  of  blue,  red  and 
green  often  return  long  before  the  complete  subsidence  of  an 
accompanying  choked  disk  (Figs.  1  and  2).  Failure  to  investi- 
gate the  eyegrounds  and  plot  the, visual  fields  in  the  physical 

1  By  certain  writers  a  process  similar  to  that  which  occurs  in  the  optic  nerve  has  been 
described  for  the  acousticus  ("choked  lahyrinth"  or  "  Stauungslabyrinthe"),  hut  the 
clinical  demonstration  of  the  effects  of  such  a  process  is  inconclusive,  and  it  has 
received  no  sufficient  pathological  or  experimental  confirmation. 


GUSHING.  31 

examination  of  a  patient  the  victim  of  headaches  is  equivalent  to 
a  neglected  urinalysis  when  there  is  pain  in  the  back  and  edema 
of  the  feet. 

We  must  turn  from  these  symptomatic  manifestations  of  the 
lesion  to  see,  if  possible,  what  has  been  taking  place  within  the 
skull.  The  primary  effect  of  most  tumors  is  an  encroachment 
on  the  space  which  normally  should  be  completely  occupied  by 
the  brain  and  its  vascular  and  cerebrospinal  fluids  —  the  Raum- 
beengung  effect  of  the  Germans.  I  say  "  most  tumors,"  for 
there  are  certain  diffuse  gliomatous  growths  which  infiltrate 
and  destroy  the  nervous  tissue  as  they  advance,  and  pressure 
phenomena  may  be  absent  unless  a  sudden  hemorrhage  or 
edema  leads  to  an  abrupt  onset  of  these  symptoms,  with  the 
clinical  picture  of  apoplexy  or  thrombosis.  Indeed,  not  only 
those  of  pressure,  but  all  other  signs  may  fail  if  s\ich  a  lesion 
originates  in  a  silent  field,  or  if,  as  often  happens,  the  growth 
prove  to  be  a  glioma  which  is  traversed  by  intact  nerve 
fibers. 

The  usual  consequence,  however,  of  the  gradual  encroach- 
ment by  the  new  foreign  body  on  the  cerebral  space  fs  a  crowding 
away  of  the  neighboring  brain  substance,  which  suffers  more 
through  compression  than  from  actual  invasion  of  the  tissue. 
The  effects  of  this  process  are  felt  locally  more  than  at  a  dis- 
tance, especially  since  there  is  a  certain  degree  of  partitioning  of 
the^cranial  chamber,  so  that  the  pressure  is  more  or  less  discon- 
tinuous, owing  to  the  presence  of  the  dural  septa.  The  hind- 
brain,  for  example,  is  particularly  well  protected  by  its  sus- 
pended dural  roof  against  pressure  exerted  from  above,  and  this 
is  especially  true  in  certain  of  the  lower  animals  who  possess  an 
ossified  tentorium.  A  slowly-growing  tumor  in  a  favorable 
situation  may  often  attain  a  large  size,  the  gradual  pressure 
causing  excavation  with  atrophy  of  the  neighboring  cerebral 
substance  out  of  which  the  tissue  fluids  have  been  slowly  but 
permanently  expressed  —  for  it  must  be  remembered  that  the 
cerebral  tissue  itself  is  practically  incompressible  —  without 
seriously  jeopardizing  the  functions  of  the  remoter  portions. 

As  a  rule,  however,  the  pressure  effects  of  a  growth  are  trans- 
mitted in  some  degree  throughout  the  entire  intracranial 
chamber.  This  occurs  in  a  number  of  ways:  through  circu- 
latory stasis,  through  the  intermediation  of  the  cerebrospinal 


32  GUSHING. 

fluid  in  one  way  or  another,  and  through  dislocation  and  change 
of  position  of  the  cerebral  or  cerebellar  hemispheres. 

Circulatory  stasis  is  naturally  one  of  the  earliest  results  of 
pressure,  for  the  slightest  increase  affects  primarily  the  outflow 
from  the  veins,  whose  fluid  tension  is  normally  very  low.  Ex- 
ternal evidences  of  this  stasis  are  not  only  observable  in  the 
eyegrounds,  but  are  also  shown  by  a  fullness  of  the  extracranial 
vessels  of  the  scalp  and  eyelids,  whose  content  normally  passes 
in  large  part  through  the  intracranial  sinuses  on  its  way  to  the 
heart.     The  distention  in  some  cases  may  be  extreme. 

Now,  the  cerebrospinal  fluid,  which  is  constantly  being  secreted 
by  the  epenclymal  cells  lining  the  choroid  plexuses  in  considerable 
quantities  —  the  amount  being  possibly  increased  under  condi- 
tions of  venous  stasis  — normally  escapes  from  the  skull  in  large 
part,  if  not  wholly,  through  the  intermediation  of  the  arach- 
noidal villi  which  project  into  the  sinuses  and  their  dural  expan- 
sions. Hence  interference  with  the  escape  of  this  fluid  may 
occur  in  consequence  either  of  some  obstruction  to  the  free 
passage  of  blood  through  the  sinuses  —  for  it  has  been  shown 
experimentally  that  these  are  compressible  channels  —  or  of 
an  occlusion  of  the  arachnoidal  villi,  possibly  by  the  small  herniae 
of  cerebral  substance  which  Wolbach  has  demonstrated  to  be 
an  accompaniment  of  marked  degrees  of  pressure. 

In  all  cases  in  which  pressure  phenomena  are  present  and  the 
obstructed  fluid  has  acquired  an  increased  degree  of  tension,  it 
collects  and  distends  the  basilar  cysternse,  finding  its  way  into 
the  optic  sheath;  hence  the  choked  disk.  It  also  passes  into 
the  olfactory  nerves;  hence  its  occasional  escape  from  the  nares 
(rhinorrhea) ;  and  into  the  spinal  canal,  where  it  may  be  demon- 
strated under  increased  tension  if  one  wishes  to  take  the  risk 
of  performing  a  lumbar  puncture  in  these  cases.  But  back  of 
this  a  still  more  important  complication  may  arise  from  this 
stasis  of  the  cerebrospinal  fluid,  in  case  the  lesion  is  so  situated 
as  to  obstruct  the  outflow  of  fluid  from  the  ventricles  by  com- 
pression of  the  iter  or  one  of  its  foramina  of  outlet  from  the 
ventricles.  A  ventricular  distention  from  this  source  is  almost 
inevitable  at  some  stage  in  the  progress  of  subtentorial  lesions, 
though  it  is  by  no  means  confined  to  them,  for  the  iter  or  one  or 
both  foramina  of  Monro  may  become  obstructed  by  cerebral 
growths  or  even  by  those  arising  from  the  pituitary  body.     The 


GUSHING.  33 

complication,  as  would  be  expected,  always  serves  to  greatly 
exaggerate  pressure  phenomena,  which  are  often  absent  until  it 
occurs.  It  is  possible  that  the  obstructive  hydrops  of  the 
ventricles  may  lead  to  certain  recognizable  symptoms  referable 
to  the  hypophysis  itself,  a  portion  of  whose  secretion  (as  Herring 
has  shown,  and  as  we  also  have  found)  normally  passes  directly 
into  the  infundibular  prolongation  of  the  third  ventricle.  But 
this  we  will  touch  upon  in  a  later  paragraph. 

And  this  brings  us  to  the  question  of  cerebral  dislocation,  an 
important  matter,  inasmuch  as  failure  to  appreciate  its  signifi- 
cance may  lead  to  errors  of  localization  and  treatment,  and  since 
on  the  principle  of  its  occurrence  much  of  our  present  surgical 
therapy  hinges. 

For  the  purpose  of  studying  the  dislocation  effects  of  tumors, 
it  is  essential  that  the  brain  be  hardened  in  situ  before  its 
removal  (preferably  by  carotid  injections  of  formalin  into  the 
carotid)  even  at  the  sacrifice  of  the  best  methods  of  fixing  the 
tissues  for  finer  histological  study.  Furthermore,  when 
possible,  it  should  be  removed  with  its  meningeal  covering  in- 
tact. One  can  depend  upon  the  macroscopic  study  of  a  brain 
prepared  only  in  this  way  for  an  accurate  appreciation  of  the 
topographical  relations  of  the  growth,  with  the  accompanying 
dislocation  of  the  meningeal  septa,  the  degree  of  ventricular 
hydrops  and  the  extent  of  the  foraminal  herniation. 

This  last  condition  deserves  a  word  of  especial  emphasis,  for 
it  is  not  only  a  frequent  cause  of  sudden  death,  but  illustrates 
at  the  same  time  the  principle  upon  which  palliative  operations 
are  founded.  Particularly  in  the  presence  of  a  lesion  of  the 
hind-brain  with  secondary  hydrocephalus,  though  the  same 
thing  is  true  also  of  a  growth  above  the  tentorium  whose  pres- 
sure effects  are  far  reaching,  the  nervous  tissues  tend  to  become 
molded  or  herniated  into  any  defect  in  the  investing  meninges. 
At  the  foramen  magnum  is  a  natural  defect,  and,  in  consequence, 
the  bulb,  with  a  surrounding  fringe  of  cerebellum,  crowds  its 
way  through  this  opening  in  the.  effort  to  escape  from  the  pres- 
sure within  the  chamber. 

It  is  for  this  reason  that  the  sudden  withdrawal  of  fluid  from 
below  by  a  lumbar  puncture  may  lead  to  serious  bulbar  symp- 
toms from  the  local  anemia  thus  produced  by  a  further  wedging 
of  the  medulla  within  the  foraminal  ring.     The  same  thing  takes 


34  GUSHING. 

place,  of  course,  when  there  is  a  sudden  increase  of  pressure 
from  above  through  edema  or  hemorrhage  into  a  growth,  and  it 
is  well  known  that  these  bulbar  symptoms  are  the  usual  terminal 
event  in  most  cases  of  brain  tumor. ^ 

An  embarrassed,  possibly  rhythmic,  respiration  is  the  first 
evidence  of  the  medullary  compression,  an  excess  of  which  may 
suffice  to  completely  stop  spontaneous  respiratory  activity. 
Under  these  circumstances  artificial  aids  to  breathing  may  tide 
over  the  first  few  perilous  moments,  and  a  consequent  rise  in 
blood  pressure  may  reawaken  the  activity  of  the  anemic  centers. 
But  in  some  cases  spontaneous  respiration  is  never  resumed  and 
the  heart  continues  to  beat  as  an  isolated  organ  so  long  as  the 
artificial  aids  to  the  act  are  continued.  On  one  occasion  during 
the  past  winter  this  accident  occurred  before  recovery  from  the 
anesthetic  in  a  patient  subjected  to  lumbar  puncture  during  the 
course  of  an  operation,  and  after  artificial  respiration  had  been 
continued  for  twenty-eight  hours  the  craniuni  was  widely 
opened  by  a  large  osteoplastic  resection  and  the  brain  examined. 
It  was  gray  in  color,  absolutely  without  circulation,  and,  though 
after  its  exposure  some  of  the  larger  arteries  were  seen  to  fill 
and  pulsate,  there  was  no  through-and-through  circulation. 
Stimulation  of  the  exposed  motor  field  by  a  powerful  faradic 
current  failed  to  elicit  any  movements  whatsoever  on  the  contra- 
lateral side  of  the  body.  On  another  occasion  artificial  respi- 
ration with  a  tracheal  canula  and  bellows  was  continued  for  a 
period  of  three  days,  and  it  is  conceivable  that  the  cardiac 
action  might  have  been  continued  for  a  week  had  it  not  been 
finally  stopped  by  an  attempted  revival  with  adrenalin  —  death 
of  the  central  nervous  system  beyond  resuscitation  having  doubt- 
less occurred  soon  after  the  circulation  was  shut  off  from 
the  medulla.^ 

^  An  analogous  disturbance  in  the  case  of  the  pontine  centers  may  follow  the  post- 
operative dislocation  downward  of  the  mid-brain  when  a  suboccipital  exploration  has 
been  made  in  the  case  of  a  lesion  which,  lying  in  or  above  the  pons,  proves  to  be 
inaccessible. 

2  It  is  possible  that  patients  in  this  condition,  with  a  paralyzed  respiratory  center, 
might  be  revived  by  a  prompt  suboccipital  exposure  of  the  foraminal  region.  Since 
writing  the  paragraphs  above,  the  measure  has  been  successfully  carried  out  in  a  patient 
with  tumor  suffering  from  sudden  respiratory  failure,  though  not  from  a  lumbar  puncture. 
Artificial  respiration  was  promply  instituted  and  continued  for  forty-five  minutes  while 
the  imprisoned  cerebellar  margin  was  exposed  and  liberated.  There  was  an  immediate 
resumption  of  spontaneous  breathing,  and  recovery  followed.  A  cerebellar  cyst  was 
found  and  evacuated  at  a  later  sitting. 


GUSHING.  35 

On  this  same  principle  there  is  a  tendency  for  the  cortex  to 
protrude  through  and  to  enlarge  any  openings,  even  minute 
ones,  and  in  this  way  are  produced  the  small  hernise  which  have 
been  described  by  Wolbach  as  occurring  at  the  situation  of  the 
arachnoidal  villi.  These  hernise  sometimes  assume  considerable 
proportions  and  become  as  large  as  peas,  and,  if  Pacchionian 
granulations  in  adult  life  have  already  formed  at  the  situation 
■of  the  villi,  they  may  even  lead  to  complete  absorption  of  the 
immediately  adjacent  parts  of  the  cranium. 

Enlargement  of  the  head  due  to  separation  of  the  sutures, 
with  the  peculiar  change  in  the  cranial  percussion  note,  is  a  well- 
recognized  symptom  of  tumor,  particularly  when  in  young 
individuals  obstructive  hydrocephalus  has  occurred;  and  the 
widening  of  the  skull  affords  marked,  often  unexpected,  relief 
from  the  pre-existing  pressure  symptoms.  This  diastasis  of 
the  sutures,  however,  can  only  be  looked  for  in  cases  of  long- 
•continued  and  excessive  pressure,  in  which,  some  time  before 
the  bones  have  separated,  the  choked  disk  has  gone  on  to  its 
atrophic  stage ;  hence  it  is  unusual  to  find  vision  present  even  in 
very  young  children  whom  nature  has  relieved  in  this  way. 
An  equally  effective  natural  method  of  relief  may  result  from 
the  local  pressure  absorption  of  the  skull  should  a  growth  lie 
immediately  subjacent  to  it.  We  have  seen  a  number  of 
instances  of  this  —  chiefly  in  temporal  lobe  tumors  —  in  which 
the  thinned  squamous  wing  of  the  temporal  bone  has  been 
absorbed  so  that  the  mass  forms  a  protrusion  under  the  temporal 
muscle  very  similar  to  that  which  occurs  as  a  result  of  the 
palliative  operation  which  has  been  devised  with  this  particular 
■object  in  view.  The  dislocation  outward,  or  the  hernia  of  the 
brain  which  occurs  after  the  making  of  such  a  purposeful  defect, 
need  not,  to  accomplish  its  object,  occur  directly  over  the  situa- 
tion of  a  tumor,  and,  indeed,  there  are  certain  objections  to  thus 
placing  it,  for  a  sudden  dislocation  of  this  kind  has  been 
shown  to  lead  not  infrequently  to  large  extravasations  within 
the  substance  of  the  undeilying  vascular  growth,  owing  to 
the  very  change  of  position  which  was  the  object  of  the  opera- 
tion; for  this  change  of  position  can  easily  be  seen  to  favor  the 
rupture  of  the  delicate,  thin-walled  vessels  which  feed  many 
tumors. 


36  GUSHING. 

II.    THE    LOCAL   EFFEGTS    OF   TUMOES. 

Though  not  entirely  inappropriate  to  the  scope  of  this  lecture,, 
a  discussion  of  the  neurological  disturbances,  functional,  para- 
■  lytic  and  irritative,  consequent  upon  lesions  in  various  parts  of 
the  brain  would  lead  us  too  far  afield.  There  are  certain  points, 
however,  which  deserve  to  be  noted.  Localization  of  function 
in  the  cerebrum  is  a  concept  of  our  own  time,  and  that  we  are 
still  forced  to  allude  to  '^  mute  areas  of  the  brain  "  is  no  occa- 
sion for  reproach  when  the  intricate  difficulties  of  the  problem 
are  appreciated.  Accessions  to  our  knowledge  of  the  structure 
and  function  of  the  nervous  system  follow  one  another  more 
rapidly  than  is  the  case  with  any  other  organ  or  system  of  organs 
in  the  body.  The  combined  labors  of  many  lead  to  this  end, — 
investigations  into  the  finer  anatomy  of  the  nerve  cells,  intO' 
the  study  of  nerve  tracts  as  they  become  primarily  myelinized  or 
secondarily  degenerate,  into  the  effects  of  excitation  of  different 
areas  or  of  experimental  lesions  in  the  animals  nearest  man. 
Thus  the  recent  work  of  Horsley  and  his  co-workers  on  the 
accurate  subcortical  placement  of  experimental  lesions  leads 
us  to  hope  for  great  advancement  in  our  knowledge  of  function 
of  the  heretofore  inaccessible  basal  ganglia;  and  the  studies  of 
Bolk  and  Van  Rynberk  promise  to  give  us  a  knowledge  of  locah- 
zation  of  function  in  the  cerebellum  comparable  to  that  which 
we  now  possess  for  the  cerebrum. 

Man  differs  from  the  lower  animals  chiefly  in  the  greater- 
development  of  his  central  nervous  system,  and  profitable  as 
the  studies  of  cerebral  function  in  the  lower  animals  haA^e  been 
in  the  past  and  will  doubtless  always  be,  the  rapid  advancement 
in  our  knowledge  in  the  sensory  field  can  only  be  made  by  the 
study  of  the  effects  of  purposeful  lesions  on  man,  for  he  alone 
is  able  to  communicate  an  interpretation  of  his  sensations. 
Such  experiments,  of  course,  are  out  of  the  question,  and  our 
observations  must  necessarily  be  confined  to  the  detailed  inves- 
tigation of  such  symptoms  as  arise  in  the  course  of  disease,  in  the 
expectation  that  post-mortem  examinations  may  reveal  a 
sufficiently  circumscribed  lesion  to  make  the  condition  com- 
parable to  that  of  a  physiological  experiment.  This,  however, 
is  rarely  the  case,  for  by  the  time  death  occurs,  the  lesion,  par- 
ticularly if  it  be  a  tumor,  will  have  rendered  the  degenerated; 


GUSHING.  37 

pathways  so  obscure  as  to  make  their  study  unprofitable.  To 
be  sure,  the  situation  of  certain  lesions  giving  a  peculiar  symp- 
tomatology was  first  made  out  in  this  way  by  the  incomparable 
studies  of  Broca  and  of  Hughlings  Jackson,  and  much  may  still 
be  expected  from  a  similar  correlation  of  gross  pathological 
findings  with  clinical  symptoms.  How  large  a  jDart  surgery  is 
to  play  in  the  furtherance  of  our  knowledge  in  these  regards 
will  depend  upon  the  preliminary  training  in  neurology  and 
neurological  pathology  of  those  who  are  to  undertake  this  kind 
of  work.  Their  privilege  in  this  respect  must  be  regarded  as  a 
liability  rather  than  an  asset,  for  to  accept  the  opportunity  of 
advancing  knowledge  is  no  light  responsibility. 

This  point  is  well  illustrated  by  the  case  of  the  hypophysis 
cerebri,  —  the  so-called  brain  gland,  —  an  organ  until  within 
recent  times  regarded  as  a  functionless  tissue  relic  which,  ac- 
cording to  our  predecessors,  discharged  pituita  or  mucus  into 
the  nose.  It  is  the  frequent  seat  of  enlargement  and  of  tumors 
which  give  a  definite  intracranial  symptom-complex,  owing 
largely  to  the  immediate  juxtaposition  of  the  optic  chiasm. 
Physiologists  had  shown  that  an  extract  of  the  posterior  lobe 
of  the  gland  contains  a  blood-pressure-raising  principle  (Howell) 
and  causes  diuresis  (S chafer  and  Herring)  and  here  the  matter 
rested  until  the  observations  by  Paulesco  —  which  have  been 
corroborated  in  the  Hunterian  Laboratory  —  brought  out  the 
surprising  fact  that  surgical  removal  of  this  physiologically 
active  posterior  lobe  does  not  appreciably  affect  the  individual; 
whereas,  on  the  other  hand,  removal  of  the  entire  gland,  or  of 
the  anterior  lobe  alone,  leads,  usually  in  the  course  of  a  few  days, 
to  a  fatal  issue  with  a  peculiar  train  of  symptoms.  Hence  the 
pituitary  body  is  a  structure  as  vital  to  the  maintenance  of  life 
as  are  the  parathyroid  bodies  or  adrenal  glands. 

Clinical  studies,  furthermore,  have  suggested  some  intimate 
relation  between  hypophyseal  activity  and  that  not  only  of 
other  ductless  glands  (the  thyroid,  thymus,  ovary,  etc.),  but  of 
various  other  functions.  Thus  it  is  connected  in  some  way 
with  the  process  of  growth  observed  in  dwarfism,  gigantism 
and  acromegaly,  the  activity  of  the  generative  organs  (amenor- 
rhea and  sexual  infantilism),  the  deposition  of  fat  (adiposis 
dolorosa  and  Frohlich's  disease)  and  possibly  other  conditions. 
Marie's  belief  that  the  acromegaly  is  due  to  a  primary  hypo- 


38  GUSHING. 

physeal  lesion  has  not  been  uniformly  accepted,  and  those  who- 
agreed  with  him  doubted  whether  it  was  the  result  of  a  hyper- 
or  a  hypo-secretion  of  the  gland,  a  matter  which  a  single  surgical 
observation  has  served  to  conclusively  determine.  Thus 
Hochenegg  removed  a  portion  of  the  enlarged  gland  from  a 
woman  suffering  from  acromegaly,  and,  as  a  result,  not  only 
did  the  local  pressure  symptoms  disappear  and  menstruation 
return,  but  there  also  took  place  a  rapid  shrinkage  of  the  previ- 
ously hypertrophied  tissues  of  the  hands,  feet  and  face.  An 
equally  striking  result  has  followed  a  partial  hypophysectomy  in 
a  case  of  my  own. 

As  has  been  intimated  in  the  earlier  paragraphs,  it  is  possible 
that  in  almost  all  tumor  cases  the  hypophysis  suffers  to  a  certain 
degree,  and  one  might  expect  its  function  to  be  particularly 
interfered  with  when  there  is  an  obstructive  hydrocephalus,  for 
Herring  has  shown  that  the  posterior  lobe  of  the  gland  dis- 
charges its  secretion  directly  into  the  infundibular  cavity  of  the 
third  ventricle.  From  a  clinical  standpoint  it  is  suggestive  that 
amenorrhea  is  a  not  infrequent  accompaniment,  often  an  early 
symptom,  of  brain  tumor  in  women,  and  further,  that  after 
removal  of  the  growth,  or  even  after  simple  decompression,  the 
menstrual  function  may  be  resumed.  Another  suggestive- 
clinical  fact  is  the  rapid  accession  of  weight  which  is  often  seen 
after  these  operations  —  more  than  can  be  accounted  for  by 
the  withdrawal  of  drugs,  the  improved  appetite  and  cessation  of 
vomiting.  One  of  our  patients  who  had  a  cerebellar  tumor 
accompanied  by  a  low  grade  of  hydrocephalus  gained  fifty 
pounds  in  the  sixteen  weeks  following  the  extirpation  of  the 
growth.  One  is  tempted  to  speculate  upon  a  possible  connec- 
tion between  this  improvement  and  a  restored  activity  of  the 
pituitary  body,  and  it  may  be  added  that  our  autopsies  have 
invariably  shown  not  only  some  histological  alteration,  but 
more  or  less  structural  deformation  of  the  hypophysis,  particu- 
larly marked  when  there  was  some  obstructive  dilatation  of  the 
third  ventricle. 

There  are  certain  things,  however,  more  strictly  pertaining 
to  the  local  effects  of  tumors  which  I  wish  to  dwell  upon.  One 
of  them  concerns  the  relation  of  a  growth  to  the  surrounding 
structures.  It  is  well  known  that  a  lesion  which  originates, 
for  example,  in  the  bone,  the  dura  or  from  the  cerebral  nerves,. 


GUSHING.  39 

will  be  slow  to  invade  the  encephalon  itself,  however  deeply  it 
may  become  molded  from  pressure,  owing  to  the  barrier  offered 
b}^  the  delicate  leptomeninges;    also  that  the  enucleation  of 
such  a  lesion  leads  to  prompt  restoration  of  function.     On  the 
other  hand,  when  symptoms  such  as  hemiplegia,  hemianopsia 
or  aphasia  are  occasioned  by  a  new  growth  which  has  originated 
in  the  brain  substance  itself,  it  is  widely  believed  that  they  will 
inevitably  be  perpetuated  if  the  lesion  be  extirpated;   in  other 
words,  that  the  symptoms  are  the  result  of  an  anatomical  de- 
struction rather  than  a  physiological  "  block  "  of  the  pathway 
involved.     If  the   centers  themselves,   ganglionic  or  cortical, 
have  not  been  destroyed  by  pressure-anemia  or  tumor  invasion, 
the  degree  of  restoration  of  function  is  often  astonishing  and 
shows  not   only   that  pressure  disturbances   are  much  more 
common  than  destructive  ones,  but  also  that  the  power  of 
restoration  of  function  is  surprisingly  great.     In  a  patient  with 
total  hemiplegia  and  hemi-anesthesia,  after  a  subcortical  sar- 
comatous cyst  the  size  of  a  tennis  ball  had  been  removed  intact, 
there  ensued  almost  complete  restoration  of  the  contralateral 
motor  and  sensory  paralysis  in  the  course  of  two  or  three  weeks. 
We  have  also  seen  a  complete  restoration  of  previously  hemi- 
anopic  vision  in  cases  in  which  the  sight  had  been  affected  simply 
from    pressure   upon   the    optic   pathway.     The   recuperative 
powers  of  the  brain,  even  when  large  areas  of  tissue  have  been 
removed  with  a  tumor,  are  often  extraordinary;    and  as  our 
ability  to  localize  tumors  improves,  they  will  be  approached 
at  an  earlier  stage  and  there  will  be  less  Ukelihood  of  damage, 
whether  from  invasion,  long-continued  compression  or  surgical 
injury.     The  old  view  that  lesions  limited  to  the  paracentral 
convolutions  which  called  early  attention  to  their  presence  by 
the  motor  irritation  or  paralysis  were  alone  suitable  for  surgical 
attack  is  rapidly  being  superseded. 

The  difficulties  of  making  a  local  diagnosis  of  a  lesion  advance 
rapidly  with  the  appearance  of  general  pressure  symptoms, 
supposed  by  many  to  be  essential  for  the  making  of  a  diagnosis 
at  all.  It  will  be  long,  I  fear,  before  physicians  will  awake  to 
this  fact.  In  many  ways  the  general  pressure  phenomena 
rapidly  obscure  the  main  issue,  and  through  distant  edemas 
through  dislocations,  through  ventricular  hydrops  and  what 
not,  secondary  or  indirect  symptoms  (Fernsymptome)  are  pro- 


40  GUSHING. 

duced  which  greatly  confuse  the  primary  focal  manifestations. 
Then,  too,  the  patient's  mental  processes  invariably  become 
affected  in  some  degree,  and  when  blindness  has  ensued,  the 
difficulties  may  be  still  further  increased.  In  illustration  may 
be  mentioned  the  case  of  a  small  boy  in  whom,  owing  to  head- 
aches, a  tumor  had  long  been  suspected,  but  no  careful  neuro- 
logical study  had  been  made  until  his  failing  vision  had  gone  on 
to  blindness.  At  this  stage  he  was  first  thoroughly  examined, 
with  an  operation  in  view,  and  the  only  focal  symptoms  were 
suggestive  of  a  lesion  of  the  left  cerebellar  hemisphere,  which 
on  two  occasions  was  thoroughly  exposed  and  examined.  He 
subsequently  died,  two  years  after  the  first  onset  of  symptoms, 
and  an  operable  benign  tumor,  such  as  would  unquestionably 
have  produced  an  homonymous  hemianopsia  as  its  earUest 
symptom,  was  disclosed  at  autopsy  in  the  left  occipital  lobe. 
The  growth  had  slightly  dislocated  the  tentorium  downward 
and  occasioned  the  left  cerebellar  symptoms.  Many  other  illus- 
trations of  this  sort  might  be  given. 

One  may  say,  therefore,  that  the  more  pronounced  the 
general  pressure  symptoms  —  the  phenomena  characteristic 
of  tumor  —  the  less  the  likelihood  of  making  the  focal  diagnosis 
which  is  essential  to  the  success  of  the  only  curative  therapeutic 
measure, —  removal  of  the  lesion. 

III.    THE    HISTOLOGICAL   PATHOLOGY   OF   TUMORS. 

And  now,  after  these  general  words  as  to  what  the  tumor  does 
and  where  the  tumor  lies,  remains  the  final  and,  possibly,  in 
view, of  the  foundation  upon  which  this  lecture  is  given,  the 
more  interesting  question  of  what  the  tumor  is.  On  this  matter, 
unhappily,  I  feel  far  less  competent  to  speak. 

Needless  to  say,  except  in  the  case  of  evident  metastases 
from  a  maUgnant  growth  elsewhere  ^  and  of  the  occasional 
undoubted  syphiloma  or  solitary  tubercle,  in  which  the  history 
is  clear  or  concomitant  foci  of  disease  are  recognized,  a  patho- 
logical diagnosis  before  the  lesion  can  be  seen  and  handled  is 
difficult  in  the  extreme,  even  though  certain  growths  have 

1  Of  these  I  have  encountered  six  during  the  past  year, —  a  melanotic  sarcoma  from, 
an  unrecognized  primary  melanoma  of  the  ovary,  a  cystic  sarcoma  secondary  to  a  growth 
in  the  neck,  and  four  instances  of  carcinoma  occurring  some  years  after  a  radical  opera- 
tion for  cancer  of  the  breast. 


GUSHING.  41 

certain  seats  of  predilection.  Indeed,  it  is  often  difficult  to 
tell  whether  the  general  and  local  symptoms  are,  after  all, 
actually  due  to  a  new  growth,  for  thej^  may  be  closely  simulated 
by  a  formidable  array  of  lesions ;  by  vascular  disease  —  throm- 
bosis, embolism,  aneurism,  even  apoplexy;  by  the  edemas  of 
nephritis,  which  may  give  characteristically  focal  symptoms; 
by  certain  chronic  inflammations  such  as  those  of  the  ependyma, 
which  may  occlude  some  foramen  of  outlet  for  the  cerebrospinal 
fluid;  and  lastly,  by  certain  post-traumatic  cysts.  Further- 
more, there  is  a  group  of  cases  —  the  so-called  pseudo-tumors 
of  Nonne  —  in  which  careful  post-mortem  studies  have  revealed 
no  lesion  whatsoever,  though  the  ante-mortem  symptoms, 
general  and  focal,  were  definitely  characteristic  of  tumor. 

But  the  difficulties  do  not  end  with  the  clinical  diagnosis; 
they  follow  us  to  the  laboratory,  where  the  dissimilarity  of  the 
growths,  even  those  which  from  a  cytological  standpoint  evi- 
dently belong  in  the  same  group,  makes  a  satisfactory  termin- 
ology often  troublesome,  sometimes  impossible.  One  important 
thing  has  been  pointed  out  by  Dr.  F.  B.  Mallory,  and  that  is  the 
necessity,  for  satisfactory  microscopical  studies,  of  the  imme- 
diate fixation  of  absolutely  fresh  tissue;  and  such  material 
in  the  case  of  brain  tumors  —  indeed,  in  many  others  —  can  only 
come  through  the  intermediation  of  surgery.  Dr.  Adolph 
Meyer,  too,  has  strongly  emphasized  the  need  of  making  sections 
of  the  entire  tumor,  for  in  the  same  growth  areas  of  widely 
different  histological  character  are  to  be  seen. 

When  one  considers  the  difficulties  of  satisfactorily  classi- 
fying, for  example,  the  various  epithelial  tumors  of  the  mam- 
mary gland, —  tumors  which  in  a  fresh  state,  in  large  numbers 
and  in  all  stages,  are  available  for  histological  study, —  it  is 
easily  comprehended  how  much  greater  are  the  difficulties  in 
the  case  of  the  brain,  where  an  unusual  variety  of  neoplasmiS 
are  to  be  found,  epithelial  growths  arising  from  the  hypophysis 
or  choroidal  ependyma,  congenital  tumors,  the  meningeal  endo- 
thehomata,  cystic  formations  of  peculiar  and  varied  sorts,  to 
mention  but  a  few  of  the  lesions  besides  those  which  are  specific 
of  the  central  nervous  system, —  the  gliomata. 

These  very  gliomata  by  no  means  invariably  conform  to  the 
accepted  description  either  of  their  gross  or  finer  anatomy. 
They  need  not,  for  example,  infiltrate  the  brain,  for  we  have 


42  GUSHING. 

encountered  many  examples  in  our  series  of  about  one  hundred 
cases  in  which  on  all  sides  they  were  as  definitely  demarcated 
as  the  endothelial  growths  which  affect  the  brain  by  compres- 
sion rather  than  invasion.  Gliomata  seem  to  have  an  especial 
predisposition  to  cystic  degeneration,  and  it  would  seem  that 
the  entire  growth  may  at  times  become  completely  transformed 
into  a  cyst.  Instances  of  this  have  been  noted  by  Sir  Victor 
Horsley,  and  elsewhere  some  personal  experiences  of  the  same 
kind  have  been  recorded.^  Thus  on  one  occasion  a  large  inop- 
erable cerebellar  tumor,  presumably  a  glioma,  was  exposed  by 
a  suboccipital  operation.  Death  occurred  some  six  months 
later,  and  the  autopsy  disclosed  a  cavity  the  size  of  a  goose's 
egg  surrounded  by  a  thin  shell  of  cerebellum  and  filled  with  a 
semi-fluid,  grumous,  broken-down,  brownish  tissue  mass,  no 
tumor  cells  whatever  being  found  on  histological  examination  of 
the  surrounding  walls. 

Such  an  occurrence  in  the  history  of  a  cerebral  growth  is 
presumably  due  to  the  shutting  off  of  the  local  vascular  supply, 
with  death  of  the  entire  tumor  mass;  and  it  may  be  said  that 
the  centers  of  many  of  the  larger  gliomata  show,  in  like  fashion, 
a  tendency  toward  gelatinous  or  cystic  metamorphosis.  A 
process  of  this  kind  seems  to  occur  more  frequently  in  gliomata 
of  the  hemispheres,  cerebral  or  cerebellar,  than  in  those  arising 
from  the  basal  ganglia,  possibly  as  the  former  may  attain  a 
larger  size  and  their  vascularization  become  less  secure.  As 
usually  encountered,  the  cysts  contain  clear  fluid  which  often 
clots  but  otherwise  resembles  cerebrospinal  fluid.  It  seems  to 
be  secreted  in  considerable  amounts,  so  that  there  is  a  tendency 
for  the  cysts  to  refill  even  after  their  evacuation.  Studies  of  the 
cyst  wall  not  infrequently  show  in  certain  areas  a  persisting 
zone  of  new  growth,  and  the  cavity  is  usually  lined  with  a  deli- 
cate, loosely-attached  membrane.  Whether  this  represents  a 
secreting  membrane,  or  whether  the  fluid  is  merely  lymph  from 
the  adjoining  nerve-tissue  which  discharges  into  the  cyst,  can 
only  be  conjectured,  especially  since  little  is  known  of  the 
lymph-flow  in  the  tissues  of  brain  and  spinal  cord.  Cerebro- 
spinal fluid,  as  is  well  known,  will  not  be  taken  up  and  absorbed 
for  any  length  of  time  by  the  areolar  tissue.     This  has  been  well 

^Removal  of  a  Subcortical  Cystic  Tumor  without  Anesthesia.      Jour.  Am.  Med. 
Assc,  1908,  vol.  1,  p.  855. 


GUSHING.  43 

shown  by  the  futile  attempts  to  effect  its  discharge  into  the 
loose  subaponeurotic  layer  of  the  scalp  in  cases  of  hydrocepha- 
lus. For  some  days  the  scalp  remains  edematous,  but  soon  the 
fluid  becomes  confined  in  a  definite  pocket,  which  acquires  a 
smooth  endothelial  lining. 

To  further  the  progress  of  surgical  therapy  a  more  accurate 
knowledge  of  the  lymphatics  of  the  brain  and  their  relation  to 
the  cerebrospinal  fluid  circulation  is,  as  pointed  out  in  a  previous 
section,  one  of  the  present  needs  in  our  study  of  the  brain  tumor 
question,  and  the  function  of  the  much-neglected  choroid  plexus 
probably  represents  the  key  to  the  situation.  Were  it  not  for 
occasional  difficulties  on  this  score,  our  present-day  operative 
methods  would  give  almost  total  relief  to  the  pressure  phe- 
nomena and  would  permit,  in  cases  of  tumors  occupying  silent 
areas,  either  of  subsequent  enlargement  sufficient  to  call  atten- 
tion to  their  situation,  or  would  allow  time  for  degeneration  in 
the  cases  in  which  this  favorable  outcome  occurs. 

During  the  past  year  Dr.  G.  J.  Heuer  and  I  have  been  given 
the  privilege  by  the  pathological  department  of  the  hospital 
of  making  first-hand  studies  of  all  of  the  brain  tumor  cases 
which  come  to  autopsy,  and  thus  we  have  gained  the  invalu- 
able experience  of  making  our  own  gross  and  histological 
examination  of  tissues  and  of  comparing  the  findings  with  the 
results  of  our  previous  neurological  examinations.  Only  in 
this  way  can  errors  of  diagnosis  and  faults  of  surgical  therapy 
be  intelligently  correlated.  In  the  matter  of  histology,  we  have 
received  the  kind  co-operation  of  Dr.  Mallory,  and  it  is  our  hope 
that  with  his  aid  we  may  be  able  at  some  future  time  to  speak 
more  in  detail  in  regard  to  this  feature  of  the  work.  Up  to  the 
present  time  our  attention  has  been  largely  confined,  as  the 
title  of  this  lecture  indicates,  to  the  functional  disturbances 
from  tumors  occurring  in  various  regions  of  the  brain,  regardless 
of  their  anatomical  makeup. 

In  conclusion,  I  wish  to  recall  briefly  some  points  touched 
upon  in  this  lecture  that  possibly  deserve  this  additional 
emphasis. 

Contrary  to  the  common  belief,  brain  tumors  are  of  frequent 
occurrence,  and  possibly  there  is  no  disease  in  which  the  symp- 
toms are  more  often  overlooked  or  incorrectly  interpreted. 
For  the  sake  of  successful  palliative  or  curative  measures,  a 


44  GUSHING. 

precocious  diagnosis  is  necessary,  and  a  careful  clinical  study 
of  all  suspected  cases  at  an  early  stage,  with  a  more  intimate 
knowledge  of  the  local  and  general  pressure  phenomena,  will 
tend  toward  this  desired  goal. 

A  more  widespread  familiarity  with  the  early  appearance  of 
the  neuroretinal  edema  and  congestion  is  needed,  and  also  the 
understanding  that  this  condition  is  merely  a  stage  in  the  process 
of  choked  disk.  Inversion  or  interlacing  of  the  boundaries  of 
the  color  fields,  heretofore  regarded  as  pathognomonic  of 
hysteria,  has  been  found  to  be  a  fairly  constant  early  phenome- 
non in  tumors. 

One  recognized  characteristic  of  the  brain  under  pressure  is 
its  tendency  to  herniate  through  a  cranial  defect,  and  as  there 
is  normally  an  opening  at  the  foramen  magnum,  a  certain  degree 
of  protrusion  is  usually  present  there.  In  the  presence  of  such 
a  condition,  the  withdrawal  of  the  cerebrospinal  fluid  from  the 
spinal  meninges  by  a  lumbar  puncture  is  often  hazardous,  as 
it  may  tend  to  a  sudden  wedging  of  the  bulb  in  the  opening, 
with  anemia  and  paralysis  of  the  vital  centers. 

The  pituitary  body  proves  to  be  one  of  the  most  important 
of  the  ductless  glands.  It  not  only  may  be  the  primary  seat 
of  a  new  growth,  but  in  the  case  of  intracranial  tumors  else- 
where, particularly  when  they  are  accompanied  by  hydro- 
cephalus, its  function  may  secondarily  become  disturbed  in 
ways  which  are  clinically  recognizable. 

The  conducting  paths  in  the  brain  are  more  often  affected  by 
simple  pressure  from  tumors  than  by  actual  destruction,  and 
the  removal  of  the  growth  or  simple  reHef  from  pressure  may 
often  lead  to  a  surprisingly  rapid  restoration  of  function. 

For  an  accurate  focal  diagnosis,  a  thorough,  early  examina- 
tion is  often  necessary,  for  with  an  advancing  lesion  symptoms 
at  a  distance  may  greatly  confuse  the  clinical  picture.  A 
considerable  percentage  of  cases  that  present  themselves  for 
surgical  treatment  are  so  nearly  blind  that  a  study  of  the  visual 
fields,  which  should  be  one  of  the  most  helpful  locaUzing  signs, 
is  precluded. 

From  a  histological  point  of  view  the  classification  of  brain 
tumors  is  most  unsatisfactory,  and  the  general  behavior  and 
manner  of  growth  of  many  of  them  does  not  conform  with 
accepted  views.     Some  gliomata  may  be  definitely  encapsu- 


GUSHING. 


45 


lated  and  favorable  for  operative  removal,  and  many  tumors 
of  this  supposedly  malignant  type  may  undergo  cystic  degen- 
eration or  gelatinous  transformation. 


46 


GUSHING. 


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The   Etiology  of   Tumors   Considered   from   the 

Standpoint  of  Congenital  Tumors  and  Tumors 

Following  Repeated  Injuries.* 

BY  S.  B.  WOLBACH,  M.D., 

ALBANY,    N.    T., 
Director  of  the  Bender  Laboratory. 

Up  to  the  present  time,  four  important  hypotheses  of  tumor 
origin  have  been  advanced:  those  of  Cohnheim,  Ribbert  and  Von 
Hansemann,  and  that  of  the  parasitic  origin  of  tumors.  These 
hypotheses  are  important  because  each  one  has  stimulated 
investigation  and  so  has  indirectly  contributed  to  the  advance- 
ment of  knowledge  in  this  great  subject. 

The  hypothesis  of  parasitic  origin  of  tumors  has  had  its  day, 
because,  subject  to  direct  experimental  test,  it  has  been  found 
incapable  of  proof  and  inadequate  to  explain  many  facts  dis- 
closed in  recent  investigations. 

I  shall  state  briefly  and  in  broad  terms  the  hypotheses  of 
Cohnheim,  Ribbert  and  Von  Hansemann  because  the  contents 
of  this  paper  deal  with  each  one  and  because  each  one  has  a  basis 
founded  upon  established  biological  facts  and  principles. 

Cohnheim's  hypothesis  is  that  tumors  take  origin  from  cells 
"  which  in  the  course  of  development  have  been  displaced  from 
their  normal  relationship,  or  have  failed  to  undergo  a  normal 
atrophy."  The  existence  of  groups  of  such  cells  or  "  embryonal 
rests  "  in  the  infant  and  adult  bodies  is  not  a  rare  occurrence,  as 
I  shall  show  below.  This  hypothesis  did  not  attempt  to  ex- 
plain why  the  isolated  cells  take  on  aberrant  growth,  or  why 
so  few  out  of  the  many  that  are  constantly  encountered  in 
pathological  work  become  malignant. 

Ribbert's  hypothesis  at  first  was  essentially  an  expansion  of 
Cohnheim's  and  included,  as  starting  points  for  tumors,  post- 
natal displacements  of  cells.  Recently  he  has  further  extended 
his  hypothesis  to  the  effect  that  mechanical  isolation  of  cells  is 

*  A  lecture  under  the  auspices  of  the  Cancer  Commission  of  Harvard  University, 
March  4,  1909. 

47 


48  WOLBACH. 

not  necessary,  and  gives  as  the  essential  feature  the  physiological 
isolation  of  cells  through  changed  function.  His  hypothesis 
thus  is  broadened  to  include  the  origin  of  tumors  from  cells  once 
a  part  of  normal  structures.  He  explains  the  origin  of  carci- 
noma by  the  physiological  isolation  of  epithelial  cells  brought 
about  by  primary  changes  in  the  supporting  connective  tissue; 
and  has  applied  this  explanation  to  the  origin  of  cancer  from 
embryonal  rests  as  well  as  from  normal  structures. 

Von  Hansemann's  hypothesis  states  that  the  tumor  cell  is  one 
that  has  suffered  modification  characterized  by  a  loss  of  the 
power  of  differentiation  and  the  acquisition  of  increased  powers 
of  growth.  This  condition  he  calls  anaplasia.  The  hypothesis 
does  not  explain  why  this  change  should  occur. 

CONGENITAL  TUMORS. 

The  most  important  feature  in  the  consideration  of  congenital 
tumors  is  the  fact  of  their  occurrence.  There  are  now  hundreds 
of  cases  on  record,  including  nearly  every  kind  of  malignant 
growth,  while  less  than  fifty  years  ago  Virchow  wrote  in  his 
book,  "  Die  Krankhaften  Geschwulste,"  that  "  hardly  any  cases 
of  congenital  sarcoma  are  known." 

The  congenital  tumors  may  be  divided  into  four  classes: 
(1)  the  teratomata;  (2)  the  mixed  tumors;  (3)  malignant 
timiors  of  specific  structures,  which  closely  resemble  normal 
tissues,  and  (4)  true,  simple  tumors,  including  carcinoma  and 
sarcoma. 

The  facts  known  about  the  origin  of  the  congenital  tumors 
apply  to  the  first  three  classes  and  support  the  hypothesis  of 
Cohnheim. 

Teratomata,  which  group  includes  those  cases  of  an  imperfect 
fetus  developing  in  the  body  of  a  more  or  less  perfect  fetus,  are 
known  to  take  origin  from  cells  of  a  very  early  embryonic  period, 
i.  e.,  the  blastomeres,  which  are  cells  capable  of  giving  rise  to  all 
types  of  tissues.  Misplacement  of  blastomeres  has  been  ob- 
served and  may  be  produced  experimentally  in  the  lower  ani- 
mals, causing  the  production  of  monstrosities.  In  this  way  the 
occurrence  of  teratomata,  containing  representatives  of  every 
tissue  in  the  body,  in  such  places  as  the  mediastinum  and 
cranium,  as  well  as  in  the  ovaries  and  testicles,  may  be  accounted 
for. 


WOLBACH.  49 

The  origin  of  the  simpler  mixed  tumors,  such  as  those  of  the 
kidney  and  parotid  gland,  may  be  traced  to  isolation  of  cells  at 
a  later  period  of  growth.  For  example,  the  kidney  develops  by 
a  very  complicated  process,  as  follows:  The  Wolffian  body,  or 
primitive  kidney  region,  gives  rise  first  to  the  myotome,  from 
which  at  a  later  period  the  nephrotome,  or  matrix  for  the  kidney 
tissues,  arises.  The  myotome  also  gives  rise  to  the  sclerotome, 
from  which  develop  striated  muscle,  bone  and  connective  tissue. 
The  finding  of  tumors  in  the  kidney  containing  bone,  muscle 
and  primitive  kidney  tissues  can  only  be  explained  by  the 
assumption  that  cells  capable  of  giving  rise  to  these  various 
tissues,  i.  e.,  those  of  the  myotome,  have  been  isolated  and 
carried  along  in  the  developing  kidney.  A  similar  explanation 
is  offered  for  the  origin  of  the  mixed  tumors  of  the  parotid  to  the 
effect  that  cells  of  the  primitive  epiblast,  whence  develop  bone, 
cartilage  and  gland  structures,  have  become  isolated  and 
included  in  the  region  of  the  developing  parotid  gland. 

In  the  human,  isolated  groups  of  cells,  or  embryonal  rests, 
have  been  found  in  many  regions.  In  the  skin,  rests  occur  as 
pigmented  nevi,  or  moles.  Malignant  tumors  frequently  take 
origin  in  these  moles.  In  the  female  genitalia,  rests  are  of  very 
frequent  occurrence,  and,  according  to  their  location,  may  be 
referred  back  to  the  Wolffian  ducts  or  to  Miiller's  ducts.  Tera- 
tomata  of  the  ovaries  in  infants  have  been  described,  and  sar- 
coma of  the  vagina  is  most  frequent  in  infancy  and  early  child- 
hood, and  has  been  found  at  birth.  These  '^  sarcomata " 
of  the  vagina  may  contain  nests  of  epithefium  and  striped  • 
muscle.  Recurrence  after  removal  is  common.  Invasion  of 
surrounding  tissue  is  the  rule,  while  metastases  are  rare. 

MaHgnant  tumors  in  infants  in  the  region  of  the  sacrum  and 
coccyx  are  relatively  frequent.  Many  of  them  contain  tissue  of 
nervous  origin  and  hence  must  arise  from  remains  of  the  neural 
canal.  Such  remains  have  been  demonstrated  in  otherwise 
normal  fetuses  by  Dr.  Mallory. 

It  is  not  rare  to  find  at  autopsy  small  inclusions  of  adrenal 
tissue  in  the  kidney,  and  this  furnishes  another  instance  of 
demonstrable  rests  of  tissue  in  an  organ  where  malignant 
tumors  of  similar  tissue  are  of  frequent  occurrence. 

It  is  almost  certain  that  the  multiple  chondromata  take  origin 
in  rests  of  cartilage  tissue,  rests  of  which  have  been  demonstrated. 


50  WOLBACH. 

In  addition  to  the  evidence  supporting  Cohnheim's  hj^pothesis, 
to  be  found  in  the  occurrence  of  rests  of  tissue  of  a  type  in  organs 
where  malignant  tumors  representing  a  similar  type  of  tissue  are 
frequently  found,  we  have  the  further  evidence  of  the  associa- 
tion of  congenital  tumors  with  anatomical  defects  of  develop- 
ment. 

Twenty-five  cases  of  mixed  tumors  of  the  kidnej^  have  been 
associated  with  congenital  defects  of  the  brain  {"  hypertrophic 
tuberous  cerebral  sclerosis  ").  Congenital  tumors  of  heart 
muscle  are  usually  associated  with  other  congenital  defects  such 
as  spina  bifida  and  cerebral  sclerosis.  One  case  which  I  reported 
was  associated  with  spina  bifida  and  multiple  nests  of  neuroglia 
tissue  in  the  meninges  of  the  spinal  cord.  A  large  proportion 
of  supernumerary  and  accessory  ovaries  have  been  the  seat  of 
tumors.  One  case  of  a  congenital  heart  lesion  (an  imperfect 
interventricular  septum)  in  a  young  adult,  autopsied  at  the 
Boston  City  Hospital,  had  a  myoma  of  the  intestine. 

Certain  tumors  are  more  common  in  infants  and  children  than 
in  adults.  These  are  the  tumors  of  the  eye  (retinal  glioma)  and 
the  mixed  tumors  of  the  kidney.  They  are  also  by  far  the 
commonest  tumor  of  infants,  which,  considering  the  complicated 
development  of  these  organs  on  the  basis  of  Cohnheim's  hj^- 
pothesis,  is  to  be  expected. 

True  sarcoma  and  carcinoma  are  rare  in  infants.  Malignant 
tumors  in  infants  are  generally  reported  as  sarcomata,  probably 
simply  because  the  cells  are  of  indeterminate  type,  representing 
as  they  do  cells  of  an  earty  period  of  development.  A  fact  of 
interest  is  that  many  cases  of  carcinoma  of  the  appendix  have 
occurred  during,  or  before,  the  adolescent  period,  and  the 
majority  before  the  age  of  forty.  As  the  appendix  is  a  rudi- 
mentary organ,  it  seems  rational  that  the  epithelial  tumors 
occurring  there  should  make  their  appearance  in  early  life. 

The  above  cursory  treatment  of  the  subject  of  congenital 
tumors  is  sufficient  to  show  that  Cohnheim's  hypothesis  is 
strongly  supported.  The  most  frequent  occurrence  of  tumors 
in  early  life  in  organs  of  very  complicated  development,  as  the 
eye  and  kidney;  the  association  of  congenital  tumors  with 
anatomical  malformations  or  vice  versa;  and,  finally,  the 
frequently  demonstrated  presence  of  remains  of  embryonal 
structures  in  man}'  locations,  all  urge  the  belief  that  the  tumors 


WOLBACH.  51 

of  early  life  develop  from  embryonal  rests.  But  so  far  nothing 
has  been  offered  in  explanation  why  these  isolated  cells  and 
structures  take  on  maHgnant  properties.  Ribbert  has  suggested 
that  the  products  of  metabolism  of  such  isolated  cells  may 
influence  the  surrounding  connective  tissue  in  a  deleterious 
manner  and  thus  excite  a  series  of  changes  which  by  their  reac- 
tion upon  the  cells  of  the  rest  may,  after  months  or  years,  bring 
about  malignant  properties.  Some  support  for  Ribbert's 
suggestion  may  possibly  be  found  in  the  matter  presented  in  the 
second  part  of  this  paper. 

TUMORS  FOLLOWING  REPEATED  INJURIES. 

The  term  "  injuries  "  is  used  here  in  a  very  broad  sense. 
Under  this  title  I  shall  discuss  the  association  of  carcinoma  with 
well-known  pathological  processes  and  those  carcinomata 
associated  with  unusual  occupations  and  peculiar  practices. 
For  the  purposes  of  approach  and  introduction,  it  is  now  neces- 
sary to  consider  some  of  the  effects  upon  epithelium  of  patho- 
logical processes  of  long  duration. 

METAPLASIA    OF   EPITHELIUM. 

The  so-called  metaplasia  of  epithelium  as  a  result  of  patho- 
logical processes  consists  chiefly  in  the  change  from  the  mucous 
variety  of  epithelium  to  the  stratified  squamous  type  and  in  the 
production  of  exuberant  growth  with  altered  structural  and 
cell  characteristics. 

The  simplest  example  of  the  change  from  the  mucous  to  the 
squamous  type  is  seen  in  eversion  of  the  uterus,  where  the 
mucous  membrane  after  a  time  changes  from  the  columnar  type 
to  a  stratified  squamous  epithelium  of  which  the  outer  layers 
may  show  a  definite  horny  change  like  that  found  in  the  normal 
epidermis. 

In  ordinary  chronic  inflammatory  processes,  including  sup- 
puration, a  similar  change  may  occur  in  certain  organs.  The 
conjunctiva  may  become  thick  and  stratified  in  chronic  conjunc- 
tivitis. The  mucous  membrane  of  the  turbinate  bones  and  of 
the  accessory  sinuses  of  the  nose,  particular!}^  in  the  antrum  of 
Highmore,  may  undergo  a  similar  change  in  chronic  inflamma- 
tions. In  the  middle  ear,  in  chronic  suppurative  processes  with 
granulation  tissue,  the  production  of  horny  squamous  epithelium 


52  WOLBACH. 

may  be  so  great  as  to  give  rise  to  solid  tumor-like  masses  com- 
posed of  horny  desquamated  epithelium,  the  so-called  pearl 
tumors,  or  cholesteatomata.  Similar  accumulations  of  horny 
epithelium  have  been  found  in  the  ureters  in  the  presence  of 
calculi.  In  the  gall  bladder,  in  chronic  inflammation,  with  or 
without  the  presence  of  calculi,  the  mucous  membrane  may 
become  transformed  to  the  squamous  type  and  there  may  also 
be  small  pendulous  outgrowths  (condyloma). 

In  chronic  inflammations  of  the  larynx,  trachea  and  bronchi, 
patches  of  squamous  epithelium  are  often  found,  and  in  a  few 
instances  where  such  patches  in  the  larynx  could  be  observed, 
papillomata  and  carcinoma  have  been  found  to  arise  in  these 
areas.  At  autopsy,  cases  of  benign  and  malignant  epithelial 
growths  of  the  respiratory  tract  have  been  found  associated  with 
multiple  patches  of  squamous  epithelium. 

The  change  from  squamous  .epithelium  to  the  columnar  type 
has  been  found  in  the  bladder  and  in  the  membranous  and 
prostatic  urethra,  often  attended  with  papillary  outgrowths. 
In  the  bladder  these  papillary  epithelial  growths  are  quite 
common  following  chronic  cystitis  of  many  years'  duration, 
and  not  rarely  they  are  associated  with  malignant,  epithelial 
growths. 

Experimentally,  the  mucous  membrane  of  the  stomach  in 
rabbits  has  been  made  to  undergo  the  change  from  the  normal 
into  stratified  squamous  epithelium. 

HETEROTROPHIC    PROLIFERATION    OF    EPITHELIUM    IN    CHRONIC 
INFLAMMATORY    PROCESSES. 

The  facts  presented  under  this  heading  are  taken  from  a 
paper  by  Lubarsch,  who  defines  the  term  "  heterotrophic  pro- 
liferation "  as  meaning  the  occurrence  of  epithelium  where  it 
positively  does  not  belong.  In  speaking  of  the  intestinal  tract, 
he  limits  the  application  of  the  term  to  those  cases  where  the 
epithehum  is  found  between  the  bundles  of  the  muscularis 
mucosae  or  completely  beneath  it. 

Every  pathologist  is  familiar  with  this  condition  and  with 
the  difficulty  of  distinguishing  microscopically  between  this 
inflammatory  growth  and  carcinoma.  Usually  the  history  of 
the  case  and  the  macroscopic  appearance  make  the  diagnosis 
easy.     The  occurrence  of  heterotrophic  growths  is  most  com- 


WOLBACH.  53 

mon  in  the  aged  and  is  always  the  result  of  deep-seated  chronic 
inflammatory  processes.  Usually  gland-like  structures  are 
reproduced  in  the  down  growths.  There  may  be  separation  of 
the  down  growth  from  the  surface  epithelium,  and  the  cells 
may  or  may  not  show  evidences  of  growth. 

In  the  series  of  cases  presented  by  Lubarsch,  there  were 
52  cases  of  heterotrophic  proliferation  of  the  stomach  epi- 
thelium, attended  either  by  hypertrophy  or  atrophy  of  the 
mucosa  as  a  whole;  the  average  age  was  sixty-two  to  sixty- 
four  years.  From  the  intestinal  tract  there  were  32  cases, 
all  associated  with  deep-seated  inflammatory  processes,  such 
as  tuberculosis  and  dysentery.  The  average  age  was  fift}'" 
years. 

From  the  gall  bladder  there  were  36  cases,  with  an  average 
of  fifty-six  years.  Nine  of  these  cases  showed  such  extreme 
thickening  and  down  growth  that  the  condition  was  a  difficult 
one  to  distinguish  from  tumor,  except  for  the  obvious  associa- 
tion with  chronic  inflammatory  processes. 

These  results  were  carefully  controlled  by  Lubarsch,  who 
excluded  the  possibility  of  embryonal  rests  being  mistaken  for 
islands  of  heterotrophic  proliferation  by  a  thorough  search  for 
embryonal  rests  in  normal  organs.  The  results  were  practically 
negative  for  the  organs  examined,  which  were  the  gall  bladder, 
stomach,  appendix,  cecum,  anus  and  rectum. 

THE  ASSOCIATION  OF  METAPLASIA  AND  HETEROTROPHIC  PROLIF- 
ERATION   OF    EPITHELIUM    WITH    CARCINOMA. 

There  is  a  fairly  well-established  association  of  carcinoma 
of  the  respiratory  passages  and  of  the  urinary  bladder  with 
processes  attended  by  metaplasia  of  the  epitheUum. 

In  Lubarsch's  series,  59%  of  the  cases  showing  heterotrophic 
proliferation  had  carcinoma  in  some  organ.  There  were  9 
cases  of  carcinoma  of  the  esophagus,  7  of  the  stomach,  4  of  the 
intestines,  3  of  the  uterus,  2  of  the  gall  bladder  and  1  each  of 
the  pharynx,  bile  ducts  and  lung.  In  17  cases  heterotrophic 
proUferation  in  an  organ  was  associated  with  carcinoma  of  the 
same  organ. 

Since  heterotrophic  proliferation  is  a  condition  found  in  old 
age,  and  carcinoma  is  essentially  a  disease  of  old  age,  Lubarsch 
expresses  the  opinion  that  the  one  precedes  the  other. 


54  WOLBACH. 

From  the  pathological  side  there  is  a  fairly  well-established 
association  between  epithelial  changes  produced  by  long- 
standing inflammatory  processes  and  the  occurrence  of  car- 
cinoma. I  shall  now  take  up  the  consideration  of  cases  in 
which  the  association  is  clinical,  though  in  some  instances 
corroborated  by  pathological  investigation. 

CAKCINOMA  FOLLOWING  WELL-KNOWN  PATHOLOGICAL  PROCESSES. 

Tumors  of  all  varieties  have  repeatedly  been  referred  back 
to  traumatism  as  an  exciting  cause.  It  is  needless  to  consider 
seriously  any  of  the  single  published  cases,  of  which  there  are 
a  great  number,  attributing  the  cause  of  a  malignant  growth 
to  a  single  traumatism.  However,  there  is  among  clinicians 
a  firm  belief  that  certain  pathological  conditions  are  responsible 
for  tumor  production.  The  very  superficial  investigation  I  have 
made  into  the  foundations  for  this  belief  indicate  that  the 
question  is  an  important  one  and  worthy  of  very  careful  investi- 
gation by  pathologists  engaged  in  cancer  research. 

Carcinoma  of  the  uterus.  —  Cullen,  in  his  book  on  "  Cancer 
of  the  Uterus,"  discusses  the  etiology  from  the  standpoints  of 
trauma,  heredity,  embryonic  cell  inclusion,  Ribbert's  theory, 
parasitic  origin  and  cancer  as  a  primary  disease  of  epithelium. 
From  his  careful  study  of  a  small  number  of  cases  of  squamous- 
cell  carcinoma  of  the  cervix  (fourteen)  he  comes  to  the  conclu- 
sion that  "  the  injuries  incidental  to  labor  have  a  potent  influ- 
ence in  the  development  of  this  variety  of  cancer."  This  seems 
to  be  the  opinion  of  many  eminent  and  conservative  gynecolo- 
gists. The  association  of  cancer  of  the  body  of  the  uterus  and 
pregnancy  is  not  so  apparent,  though  Cullen's  series  of  19 
carefully-studied  cases  shows  an  apparent  connection  between 
childbearing  and  cancer  of  the  body  of  the  uterus. 

Carcinoma  of  the  stomach,  gall  bladder  and  bronchi.  —  Support 
for  the  belief  of  origin  of  carcinoma  of  these  organs  in  ordinary 
pathological  processes  is  furnished  by  the  pathological  studies 
of  Haberfeld.  From  20,000  autopsies  there  were  662  cases  of 
carcinoma  of  the  stomach,  106,  or  16%,  of  which  could  be  proved 
to  have  been  preceded  by  ulcer.  Inasmuch  as  there  was  no 
way  of  determining  the  precedence  of  ulcer  in  the  other  cases, 
he  concludes  that  there  must  be  a  connection  between  carcinoma 
and  ulcer  of  the  stomach.     The  connection  between  cholelithi- 


WOLBACH,  55 

asis  and  carcinoma  of  the  gall  bladder  is  more  evident.  Out  of 
265  cases  of  gallstones  in  20,000  autopsies,  27%  were  in  males, 
73%  in  females.  In  the  same  series  of  autopsies  there  were 
164  cases  of  carcinoma  of  the  gall  bladder,  of  which  27%  were 
in  males  and  73%  in  females.  In  98  cases  of  gall-bladder  car- 
cinoma collected  from  other  authors,  there  were  68  cases  with 
cholelithiasis,  an  average  of  70%.  Haberfeld  argues  that 
gallstones  were  found  almost  without  exception  in  cases  of 
primary  carcinoma  of  the  bladder,  while  in  secondary  car- 
cinoma they  are  very  rare.  The  strongest  argument  he  ad- 
vances for  the  connection  between  the  two  conditions  is  that 
the  ratio  of  carcinoma  of  the  gall  bladder  in  the  two  sexes  is 
exactly  the  same  as  in  the  case  of  gallstones.  He  concludes 
that  the  relationship  of  carcinoma  to  gallstones  is  inevitable. 

As  an  introduction  to  the  statistics  of  carcinoma  of  the 
bronchi,  Haberfeld  calls  attention  to  the  fact  that  the  right  lung 
during  j^outh  is  more  often  affected  by  diseases  than  the  left. 
This  he  largely  attributes  to  the  anatomy  of  the  bronchi,  and 
lays  stress  upon  the  straighter  line  made  by  the  right  primary 
bronchus  w^ith  the  trachea.  He  thinks  that  the  right  bronchi 
and  lung  are  more  exposed  to  injurious  agents  than  the  left. 
The  type  of  injury  is  not  that  directly  due  to  inhalation  of  solid 
particles  and  injurious  gases,  but  to  the  resultant  secondary 
infectious  processes.  Since  males  are  more  exposed  than 
females,  cancer  of  the  bronchi  should  be  more  common  in 
males,  and  this  is  shown  by  the  193  cases  he  collected  from 
his  own  series  and  those  of  four  other  authors,  in  which  155  were 
in  males  and  38  in  females.  The  more  frequent  occurrence  of 
carcinoma  in  the  right  side  also  supports  the  belief  in  the  con- 
nection between  injury  and  carcinoma.  Thus,  out  of  146  cases 
collected,  94  were  primary  on  the  right  side,  41  on  the  left  side. 
In  9  cases  there  was  bilateral  carcinoma. 

Histologically,  the  68  cases  in  Haberfeld's  series  were  mostly 
of  the  squamous-cell  type,  so  that  the  argument  is  suggested 
that  the  same  causes  that  produce  the  squamous-cell  meta- 
plasia of  the  bronchial  epithelium  are  responsible  for  the 
production  of  carcinoma. 

Carcinoma  of  the  breast.  —  The  association  of  chronic  mastitis 
and  carcinoma  of  the  breast  is  firmlv  fixed  in  the  minds  of  sur- 


56  WOLBACH. 

geons,  and  the  pathologist  when  examining  micros copicall}- 
cases  of  chronic  mastitis  is  often  confronted  by  masses  of  epi- 
thelial cells  hard  to  distinguish  from  carcinoma.  In  these  cases 
there  may  be  marked  epithelial  proliferation  and  changes  in 
cell  characteristics  with  the  production  of  cell  masses  which 
resemble  carcinoma  in  every  way,  except  in  evidences  of 
invasion. 

A  recent  analysis  of  100  cases  of  carcinoma  of  the  breast  by 
Leaf  gives  the  following  results*  Eighty-four  per  cent  were 
married  women;  the  remaining  16%  were  unmarried.  Seventy- 
one  per  cent  of  the  100  cases  gave  histories  of  abnormal 
lactation  characterized  either  by  over-lactation  or  under-lacta- 
tion.  Thirty-five  per  cent  showed  a  definite  history  of  injury, 
and  in  32%  the  carcinoma  developed  in  the  injured  side.  The 
average  duration  of  time  after  injury  before  the  carcinoma  was 
noticed  was  three  5'ears  and  two  months.  Twenty-three  per 
cent  of  the  100  cases  had  a  family  history  of  carcinoma. 

Carcinoma  of  the  'penis.  —  Chronic  balanitis  is  invariably 
given  as  the  most  important  etiological  factorm  the  production 
of  carcinoma  of  the  penis.  The  statistical  evidence  for  this 
belief  is  wholly  of  a  negative  character,  consisting  of  the  known 
immunity  of  circumcised  races  to  carcinoma  of  the  penis.  In 
100  cases  from  the  Massachusetts  General  Hospital,  none  were  in 
Jews.  Bashford,  in  the  third  report  of  the  Imperial  Fund  for 
Cancer  Research,  says  that  carcinoma  of  the  penis  is  practically 
unknown  in  Mohammedan  races  which  practice  circumcision. 

Carcinoma  following  lupus.  —  Recently,  many  cases  of  epi- 
dermoid carcinoma  and  a  few  cases  of  sarcoma  have  been  re- 
ported in  lupus  patients.  The  tumors  develop  in  the  affected 
areas  after  many  years'  duration  of  the  disease.  The  number 
of  cases  reported  is  too  great  to  admit  of  explanation  by  coinci- 
dence. In  one  series  of  cases  of  lupus  (Wild),  five  out  of  every 
fifty  developed  carcinoma.  Furthermore,  the  very  early  age  in 
which  epidermoid  carcinoma  makes  its  appearance  in  lupus 
patients  and  the  frequent  occurrence  in  females  are  additional 
evidence  of  relationship. 

In  addition  to  the  above  conditions  associated  with  carcinoma 
and  capable  of  statistical  support,  there  are  numerous  other 
pathological  processes  which  have  long  been  associated  with 
tumor  production. 


WOLBACH.  57 

Tumors  of  the  colon  are  more  common  at  the  flexures,  and 
the  explanation  usually  given  is  that  the  feces  remain  there 
for  a  longer  time,  giving  rise  to  greater  trauma  and  absorption 
there  than  elsewhere.  The  effects  of  heat  and  volatile  sub- 
stances from  tobacco  smoking  are  popularly  supposed  to  con- 
tribute to  carcinoma  production  in  the  mouth  and  lips.  The 
name  "  scar  cancer  "  has  arisen  from  the  apparently  frequent 
development  of  cancer  in  scar  tissue.  In  syphiUtics  the  devel- 
opment of  cancers  in  patches  of  leucoplakia  in  the  mouth  has 
been  sufficiently  frequent  to  establish  a  belief  in  the  etiological 
relationship.  Finally,  we  have  the  association  of  very  simple 
chronic  inflammatory  processes  with  carcinoma  production 
in  cases  of  chronic  osteomyelitis  of  many  j^ears'  duration  when 
attended  by  a  discharging  sinus. 

CARCINOMA     ASSOCIATED      WITH     UNUSUAL     OCCUPATIONS      AND 

PRACTICES. 

Perhaps  the  best  known  of  all  occupations  associated  with 
carcinoma  is  that  of  chimney  sweeps.  The  type  of  carcinoma 
is  the  epidermoid  or  epithelioma,  which  usually  makes  its  first 
appearance  upon  the  scrotum.  The  affection  has  been  most 
common  in  England,  and  its  rarity  in  other  countries  has  been 
used  as  an  argument  against  the  causal  relationship  of  the 
occupation  to  the  disease.  A  recent  paper  by  Butlin  discloses 
the  fact  that  the  sweeps  in  England  are  notoriously  careless  in 
protecting  their  person,  while  the  sweeps  of  continental  coun- 
tries are  more  cleanty  and  wear  a  special  dress  adapted  to 
protect  them  from  the  soot  while  engaged  in  their  work. 
Chimne}^  sweep's  carcinoma  makes  its  appearance  after  many 
years  of  service  and  is  always  preceded  by  thickening  of  the 
skin,  keratoses  and  persistent  ulceration. 

Carcinoma  of  the  scrotum  is  a  rare  disease.  During  five  3'ears 
at  the  Boston  City  Hospital,  1881  to  1887,  there  was  but  1  case. 
In  twenty  years  preceding  1887,  48  cases  were  collected  in 
London,  of  which  38  or  39  were  in  sweeps.  In  4  of  the  remain- 
der, the  occupation  was  not  determined.  Of  29  cases  in  sweeps 
from  one  hospital  (St.  Bartholomew's),  21  were  below  the  age 
of  fifty.  Two  cases  were  recorded  in  men  below  the  age  of 
thirty.  Oliver,  in  his  book  on  "  Diseases  of  Occupation," 
states  that  the  mortality  among  chimney  sweeps  from  carol- 


58  WOLBACH. 

noma  for  three  years  preceding  1902  compared  with  other  occu- 
pations involving  manual  work  was  as  133  to  63.  Another  set 
of  statistics  gives  the  ratio  as  156  to  44.  These  figures  are 
significant  when  we  take  into  consideration  that  cancer  of  the 
scrotum  is  a  very  rare  disease,  and  though  it  may  be  true  that 
the  mortality  among  sweeps  from  this  disease  is  no  greater  than 
the  general  mortality  among  women  from  carcinoma  of  corre- 
sponding parts,  the  vulva,  as  claimed  by  Roger  Williams,  the 
significance  is  not  diminished.  Carcinoma  of  the  vulva  is  not 
a  very  rare  disease,  and,  therefore,  the  comparison  is  not  a  valid 
one. 

In  fact,  among  all  occupations  where  the  handling  of  products 
of  combustion  of  coal  is  a  feature,  many  cases  of  chronic  derma- 
titis leading  to  keratoses  and  carcinoma  occur.  This  association 
is  so  frequent  that  it  has  become  of  great  clinical  importance. 
The  occupations  besides  that  of  chimney  sweeping  where  soot 
or  distillation  products  of  coal  are  handled  are,  gardening,  where 
soot  is  used  to  sprmkle  plant  beds;  workers  in  carbon  factories; 
and  tar,  paraffin  and  asphalt  workers.  In  all  of  these  occupa- 
tions the  evolution  of  the  disease  is  the  same, —  chronic  thicken- 
ing of  the  skin,  keratoses,  ulceration  and,  finally,  carcinoma. 
In  all,  the  exposed  parts  only  become  affected.  In  this  country 
a  few  cases  of  carcinoma  following  the  usual  type  of  chronic 
dermatitis  have  been  reported  from  the  National  Carbon  Works. 

Aniline  workers.  —  Workmen  engaged  in  handling  aniline 
oil  products  are  particularly  subject  to  chronic  cystitis,  which 
has  been  fairly  well  proved  to  be  due  to  the  elimination  of  aniline 
derivatives  in  the  urine.  After  many  years  of  service,  a  certain 
proportion  develop  tumors  of  the  bladder,  so  that  the  associa- 
tion between  the  occupation  and  the  disease  has  become  fixed  in 
medical  literature.  Up  to  1907,  26  cases  of  bladder  tumor  have 
been  reported  in  aniline  workers.  Twenty  of  these  cases  were 
malignant.  The  time  of  exposure  varied  from  five  to  twenty- 
nine  years.  The  majority  of  the  tumors  are  malignant  papillary 
growths.     A  few  have  been  reported  as  sarcoma. 

Recently  I  autopsied  a  case  of  carcinoma  of  the  bladder  in  a 
man  who  had  worked  in  an  aniline  works  for  more  than  fifteen 
years.     For  many  years  he  had  had  chronic  cystitis. 

Bilharzia  disease.  —  Bladder  tumors  are  so  common  in  persons 
with  Bilharzia  disease  that  the  causal  relationship  is  unques- 


WOLBACH.  59 

tioned.  Until  recently  the  nature  of  these  tumors  could  be 
questioned,  but  a  recent  paper  by  Goebel,  based  upon  careful 
pathological  investigation,  states  that  50%  are  malignant. 

Carcinoma  of  sailors.  —  A  few  cases  of  multiple  carcinoma  of 
the  face  in  sailors  have  been  reported  by  Unna,  who,  on  account 
of  the  sequence  of  chronic  dermatitis,  keratoses  and  carcinoma, 
thinks  that  the  disease  is  a  direct  result  of  exposure  in  susceptible 
individuals. 

"Kangri  "  carcinoma.  —  This  is  almost  the  most  striking 
instance  we  have  of  carcinoma  associated  with  a  definite  and 
peculiar  practice.  The  Kangri  is  a  small  earthenware  stove 
employed  by  the  natives  of  Kashmir  and  worn  attached  to  the 
belt  beneath  their  robes.  After  many  years  of  this  practice,  a 
chronic  dermatitis  results  which  finally  becomes  the  seat  of 
carcinoma.  Closely  allied  tribes  living  at  lower  altitudes,  who 
do  not  employ  this  method  of  keeping  warm,  do  not  have  this 
disease.  Because  of  the  extreme  rarity  of  carcinoma  of  the  skin 
of  the  abdomen,  there  can  be  no  doubt  as  to  the  causal  relation- 
ship of  the  practice  to  the  disease.  This  account  is  taken  from 
the  third  report  of  the  Imperial  Cancer  Research  Fund  of 
England. 

Two  other  striking  examples  of  carcinoma  associated  with 
definite  practices  are  also  taken  from  the  last  report  of  the 
Imperial  Cancer  Research  Fund.  These  are  the  "  Horn  Core  " 
cancer  of  cattle,  and  cancer  in  women  who  chew  preparations 
of  betel  leaves. 

The  former  is  an  epidermoid  carcinoma  beginning  at  the  base 
of  the  right  horn  of  cattle  employed  in  India  for  draft  purposes. 
The  traction  is  made  by  means  of  a  rope  attached  to  the  right 
horn  and  hence  the  evident  causal  relationship.  Carcinoma 
of  the  cheek  in  women  who  chew  betel  leaves  is  attributed  to 
the  fact  that  the  preparation  consisting  of  betel  leaves,  lime  and 
other  ingredients  is  constantly  kept  in  one  position  even  during 
sleeping  hours  between  the  teeth  and  cheek.  A  causal  relation- 
ship is  indicated  by  the  fact  that  the  tumor  develops  on  the  side 
employed  in  the  practice. 

CARCINOMA    FOLLOWING   X-RAY    EXPOSURES. 

I  have  reserved  this  subject  for  the  last  because  of  its  great 
importance  and  its  bearing  upon  the  value  of  the  other  associa- 


60  WOLBACH. 

tions  between  tumors  and  preceding  processes.  Because  of  the 
large  number  of  cases,  the  occurrence  in  young  individuals  and 
the  multiplicity  of  the  growths  upon  exposed  parts  only,  the 
causal  relationship  between  repeated  x-ray  exposures  and 
carcinoma  cannot  be  denied.  Nor  is  it  denied  by  any  who  have 
investigated  the  subject  with  care.  New  cases  are  constantly 
being  reported,  and  the  etiological  connection  between  the 
x-rays  and  carcinoma  of  the  skin  is  now  accepted  in  all 
countries. 

The  x-ray  carcinoma  is  the  first  experimental  carcinoma. 
The  subjects  have  been  men  more  or  less  constantly  exposed 
to  the  x-rays  during  working  hours.  The  evolution  of  the 
disease  has  been  carefully  observed  and  is  practically  constant 
in  all  cases.  A  few  of  the  victims  have  been  patients  subjected 
to  many  exposures  during  several  years.  Up  to  the  time  of 
writing,  thirty-six  cases  of  carcinoma  have  been  collected  and 
verified  by  microscopic  examination.  The  majority  are  cases 
of  young  individuals.  Many  have  ended  fatally  from  metas- 
tases. In  all  cases  the  tumors  have  been  multiple  upon  exposed 
portions  of  the  body  only,  —  hands,  arms  and  face.  X-ray  car- 
cinoma, then,  is  characterized  by  its  occurrence  in  young  indi- 
viduals and  by  its  malignancy.  It  develops  in  skin  which  has 
been  for  several  years  the  seat  of  a  chronic  dermatitis  character- 
ized by  telangiectases  and  keratoses. 

The  evolution  is  in  many  respects  similar  to  the  evolution  of 
carcinoma  in  sailors,  chimney  sweeps,  and  Kangri  carcinoma, 
and  great  stress  must  be  laid  upon  the  fact  that,  where  a  large 
number  of  cases  of  carcinoma  are  associated  with  a  given  occu- 
pation or  practice,  the  tumors  always  develop  on  the  part  of  the 
body  exposed  to  the  injurious  agent. 

I  have  had  an  opportunity  of  making  a  careful  study  of  cases 
of  chronic  x-ray  dermatitis,  the  material  for  which  was  supplied 
by  Dr.  C.  A.  Porter.  The  results  of  this  study  showed  that  the 
chief  effects  of  the  x-rays  were  upon  the  deep  tissues  of  the  skm, 
connective  tissues,  smooth  muscle  and  endothelium.  There  is 
repeated  destruction  of  tissue  and  repair  until  the  development 
of  obliterative  changes  in  the  vessels  prevents  normal  repair. 
Then  comes  a  stage  when  the  structure  of  the  skin  greatly 
changes,  during  which  the  epithelium  is  constantly  forced  to 
proliferate  in  order  to  repair  small  defects  caused  by  the  necrosis 


WOLBACH.  61 

of  the  underlying  tissue.  The  epithelium  is  likewise  probably 
subjected  to  veiy  marked  changes  in  nutrition.  The  importance 
of  these  findings  is  greatly  increased  by  the  fact  that  in  a  few 
cases  where  patients  were  subjected  to  a  long  period  of  expo- 
sures to  the  x-rays,  carcinoma  did  not  develop  for  a  long  time 
afterwards, —  usually  several  years.  This  so-called  latent 
period  is  against  believing  that  the  direct  action  of  the  rays  is 
the  cause  of  the  tumor  production.  The  constant  severe 
changes  existing  over  this  period  in  the  deeper  layers  of  the  skin 
have  a  marked  effect  upon  the  epidermis,  as  I  have  proved,  and 
are,  therefore,  probably  responsible  for  the  acquisition  of  new 
properties  on  the  part  of  the  epidermis. 

The  change  in  the  epidermis  is  perhaps  best  regarded  not  as 
the  acquision  of  new  properties,  but  as  a  reversion  to  an  earlier 
type  in  which  the  property  of  differentiation  has  not  been 
acquired  while  the  growth  capacity  is  at  its  maximum. 

Other  investigators  of  x-ray  lesions  and  carcinoma,  notably 
Unna,  Wyss  and  Linser,  have  come  to  a  similar  conclusion 
regarding  the  effects  of  the  rays  upon  the  skin.  All  have  found 
the  chief  effects  to  be  in  the  tissues  below  the  epidermis. 

The  conclusions  drawn  by  myself  and  other  workers  in  regard 
to  the  evolution  of  the  x-ray  carcinoma  are  of  great  importance 
because  of  the  support  they  necessarily  give  to  Ribbert's 
hypothesis. 

Goebel,  in  his  investigation  of  bladder  tumors  in  Bilharzia 
disease,  has  traced  the  first  process  back  to  the  stoppage  of 
vessels  by  the  ova  of  the  parasites.  The  first  effect  is,  therefore, 
necrosis  without  sepsis  and  followed  by  imperfect  repair.  Pro- 
liferation of  the  epithelium  is  here  also  secondary  to  connective 
tissue  changes.  It  is  maintained  by  a  long-continued,  con- 
stantly repeated  aseptic  inflammation  caused  by  the  ova  of  the 
Bilharzia  parasite. 

Goebel  finds  analogies  between  the  processes  in  Bilharzia 
disease  and  those  observed  in  aniline  workers,  tobacco  smokers, 
chimney  sweeps,  etc. 

There  is  unquestionably  a  great  similarity  between  the  pro- 
cesses in  Bilharzia  disease  of  the  bladder  and  the  x-ray  derma- 
titis. 


62  WOLBACH. 


SUMMARY. 


In  the  first  part  of  this  paper  I  have  endeavored  to  present  a 
few  data  which  support  the  beUef  that  the  congenital  tumors 
and  tumors  of  infancy  and  early  childhood  most  commonly  take 
origin  from  isolated  or  misplaced  cells.  At  least  we  have  very 
positive  evidence  that  certain  tumors,  such  as  the  teratomata, 
hypernephromata,  mixed  tumors  of  the  kidney  and  parotid  and 
the  retinal  tumors  arise  from  such  errors  of  development.  In 
the  second  part,  I  have  endeavored  to  show  that  in  the  cases  of 
x-ray  carcinoma  and  a  few  other  instances,  such  as  Bilharzia 
disease  and  Kangri  carcinoma,  there  is  a  proved  causal  relation- 
ship between  malignant  tumors  and  antecedent  pathological 
processes.  The  more  peculiar  the  source  of  the  injury,  the 
greater  is  the  value  of  the  evidence  when  the  association  is 
marked  by  a  strikingly  large  number  of  cases.  The  similarity 
in  the  evolution  of  the  skin  carcinoma  in  widely  different  kinds 
of  exposures  points  to  a  common  underlying  process  whatever 
the  nature  of  the  injurious  agent.  In  the  cases  of  x-ray  carci- 
noma, and  Bilharzia  carcinoma,  there  is  a  proved  similar  ante- 
cedent pathological  process.  X-ray  carcinoma  is  to  be  regarded 
as  the  first  instance  of  an  experimentally  produced  malignant 
tumor.  Its  occurrence  following  definite  lesions  of  the  skin,  of  a 
continuous  and  progressive  character,  places  the  whole  subject  of 
carcinomata  following  repeated  injuries  upon  a  firm  basis.  It 
designates  this  field  of  investigation  as  the  most  promising  one  for 
research  into  the  origin  of  carcinoma,  because  we  have  at  least 
one  and  perhaps  several  examples  of  proved  causal  relationship. 

The  facts  presented  do  not  speak  for  belief  in  simple  trauma 
as  a  cause  for  tumor  production.  They  do  indicate  that  long- 
continued  progressive  lesions  of  connective  tissue  supporting 
epithelium  are  responsible  for  the  acquisition  of  malignant 
properties  by  the  epithelium.  This  belief  is  not  so  far  removed 
as  it  would  at  first  appear  from  the  hypothesis  of  Von  Hanse- 
mann,  who  believes  that  the  malignant  property  of  epithelium 
is  a  primary  disease.  There  is  no  incompatibility  in  a  theory 
which  holds  to  the  idea  that  similar  properties  may  be  acquired 
by  years  of  changed  environment  and  nutrition. 

Finally,  it  may  be  said  that  no  series  of  experiments  upon 
animals,  in  the  attempt  to  produce  tumors,  has  ever  been 


WOLBACH.  63 

carried  out  which  in  aii}^  way  approached  duplication  of  those 
conditions  we  find  in  man  associated  with  the  production  of 
cancer.  The  element  of  time  is  perhaps  the  most  important 
factor.  Many  years  always  elapse  between  the  onset  of  the 
antecedent  pathological  process  and  the  occurrence  of  cancer. 
In  the  case  of  the  x-rays  ten  years  is  perhaps  the  shortest  period. 
But  the  magnitude  of  the  problem  and  the  value  of  the  results 
should  justify  the  expenditure  of  time  and  money  necessary  to 
more  adequately  investigate  this  field  of  the  cancer  problem. 

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Ribbert:  Geschwulstlehre.     Bonn,  1904. 

Ibid;  Beitrage  zur  Entstehung  der  Geschwulste.     Bonn,  1906. 

Ibid:  Zweite  Erganzung.     Bonn,  190". 

Ibid:  Dritte  Erganzung.     Bonn,  1908. 

Adami:  The  Principles  of  Pathology,  vol.  i,  1908. 

Williams:  Natural  History  of  Cancer.     1908. 

Oliver:   Diseases  of  Occupation.     1908. 

Goebel:  Ueber  Congenitales  Femur  Sarcom  geheilt  durch  operative  und  Rontgen- 
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Brienl:   Ibid. 

Herth:   Ibid. 

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Wolbach:  Congenital  Rhabdomyoma  of  the  Heart.  Jour.  Med.  Research,  vol.  xvi, 
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Fiitterer:    Ueber  Epithelmetaplasie.     Lubarsch  und  Ostertag,  1903,  part  ii. 

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Zeitschr.  fiir  Krebsforsch.,  1907. 

Tauffer:    Sarcom  auf  narbig-luposen  Boden.     Virchow's  Arch.,  sup.  to  vol.  cli. 

Spencer:  Cases  of  Lupus  becoming  Epithelioma  after  Repeated  Surgical  and  Pro- 
longed X-Ray  Treatment.     Trans.  Clin.  Soc.  London,  1906,  vol.  xxxix. 

Wild:  The  Supervention  of  Epithelioma  upon  Lupus  Vulgaris.  Publications  of  the 
University  of  Manchester,  Medical  Series  No.  8,  1908. 

Oliver:  Tar  and  Asphalt  Workers'  Epithelioma  and  Chimney  Sweeps'  Cancer. 
Brit.  Med.  Jour.,  Aug.  22,  1908. 

Butlin:  Cancer  of  the  Scrotum  in  Chimney  Sweeps  and  Others.  Ibid.,  June  and 
July,  1892. 

Leyberth:  Beitrag  zur  Kenntniss  der  Blasengesehwiilste  bei  Anilin  arbeitern. 
Miinch.  Med.  Wochenschr.,  Bd.  54,  part  ii,  1907. 


64  WOLBACH. 

Lueke:   Epithelioma  in  Carbon  Workers.     Cleveland  Med.  Jour.,  1907,  vol.  vi. 

Unna:    Carcinoma  of  Sailors.     Histopathology  of  the  Diseases  of  the  Skin. 

Haberfeld:  Zur  Statistik  und  Aetiologie  des  Carcinoma  des  Magens,  der  Gallenwege 
und  Bronchien.     Zeitschr.  fiir  Krebsforsch.,  Bd.  vii,  1908. 

Goebel:  Ueber  bei  die  BUharziakrankheit  vorkommenden  Blasentumoren  mit 
besonderer  Berucksichtigung  des  Carcinoms.     Ihid.,  Bd.  iii,  heft.  4. 

Wyss:  Zur  Entstehung  des  Rontgencarcinoms  der  Haut  und  zur  Entstehung  des 
Carcinoms  in  AUgemeinen.     Beitr.  zur  klin.  Chir.,  1906,  vol.  xlix. 

Wyss:   Zur  Entstehung  Primarer  Carcinome.     Deut.  Arch,  fiir  Chir.,  Bd.  xciii,  heft  6. 

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Dermat.  u.  Syph.,  1904,  heft  1. 

Linser:  Beitrag  zur  Histologic  der  Rontgenwirkung  auf  die  normals  menschliche 
Haut.     Fortschritte  auf  d.  Gebeite  d.  Rontgenstrahlen,  no.  8,  1904-1905. 

Unna:    Die  Chronische  Rontgendermatitis  der  Radiologen.     Ihid. 

Porter  and  White:  Multiple  Careinomata  following  Chronic  X-Ray  Dematitis.  Ann, 
Surg.,  November,  1902. 


The   Problem  of   Cancer  Considered  from  the 
Standpoint  of  Immunity.* 

BY  FREDERICK  P.  GAY,  M.D., 

BOSTON,    MASS., 
Instructor  in  Pathology,  Harvard  Medical  School. 

The  probability  of  appl.ying  the  principles  of  immunity, 
determined  by  studies  on  bacterial  infections,  to  the  problem 
of  cancer  was  not  very  great  so  long  as  this  disease  was  studied 
only  as  it  occurred  in  human  beings.  The  introduction  of 
experimental  cancer  research  in  animals  through  transmissible 
tumors  has  made  the  possibility  of  combating  this  disease  by 
means  of  vaccination  or  specific  serum  much  more  hopeful.  In 
cancer  no  parasitic  etiological  factor  has  as  yet  been  demon- 
strated, but  progress  toward  a  prevention  of  the  disease  would 
seem  at  the  present  moment  not  to  be  dependent  on  the  dis- 
cover}'' of  such  an  agent.  We  have  indeed  in  rabies  and  in 
smallpox  two  diseases  that  may  be  successfully  prevented,  and, 
if  we  regard  contagion  as  the  beginning  of  the  disease  itself, 
may  be  cured,  in  spite  of  the  fact  that  we  possess  little  or  no 
exact  knowledge  as  to  the  etiological  agent  in  either  of  these 
maladies.  We  are  not,  indeed,  it  seems  to  me,  primarily  inter- 
ested at  the  present  moment  in  discovering  the  cause  of  cancer, 
particularly  if  we  may  regard  the  tumor  itself  as  the  agent  of  in- 
fection and  the  body  of  the  host  as  a  culture  medium.    (Ehrlich. ) 

It  may  be  well,  however,  to  consider,  first,  certain  agents 
which  have  been  claimed,  and  are  still  being  claimed,  to  be  the 
cause  of  cancer,  and,  second,  to  consider  in  particular  certain 
accessory  etiological  factors  in  the  disease. 

THEORIES    OF   CANCER    ETIOLOGY. 

Bacteria  have  been  described  in  connection  with  cancer 
which  have  been  supposed,  by  certain  authors,  to  bear  an 
etiological  relation  to  the  disease.     Doyen  still  maintains  that 

*  Being  a  lecture  delivered  at  the  Harvard  Medical  School,  March  11,  1909,  as  one 
of  a  series  given  under  the  auspices  of  the  Cancer  Commission  of  Harvard  University. 

65 


66  GAY. 

his  micrococcus  neojormans  is  the  cause  of  cancer,  and  he  has 
attempted  to  treat  the  disease  in  human  beings  by  means  of  a 
serum  from  animals  that  have  been  immunized  against  this 
coccus.  Schmidt  and  others  have  described  certain  yeasts  as 
the  cause  of  cancer  and  have  claimed  to  demonstrate  their 
presence  in  cancer  tissues.  Other  authors  have  attributed  the 
etiological  role  in  cancer  to  a  protozoon,  and  various  forms  of 
organisms  of  this  nature  have  been  described  in  the  tissues. 
Borrel,  who  is  inclined  to  believe  that  some  protozoon  must 
be  the  cause  of  cancer,  admits,  notwithstanding,  that  none  of 
the  organisms  described  up  to  the  present  time  can  be  consid- 
ered as  proved  to  bear  any  relation  to  the  disease;  he  does, 
however,  regard  the  protozoon  origin  as  probable  on  account 
of  the  fact  that  cancer  histologically  would  seem  to  resemble 
other  forms  of  supposedly  protozoon  disease,  such  as  variola, 
sheep-pox  (clavelee)  and  moUuscum  contagiosum. 

Leaving  aside  these  supposed  parasitic  causes  of  cancer  thus 
summarily,  we  may  turn  to  a  brief  consideration  of  certain 
physiological  factors  or  substances  in  the  blood  which  have  been 
supposed  to  bear  some  causal  relation  to  cancer  growth.  These 
substances  may  be  grouped  under  two  general  headings:  Those 
substances  which  are  supposed  to  act  in  some  positive  manner 
in  causing  proliferation  of  epithelial  cells,  and  those  substances 
the  absence  of  which  in  animals  predisposed  to  cancer  may 
give  rise  to  the  growth  of  the  tumor. 

Starling  has  described  the  presence  of  certain  "  chemical 
messengers,"  or  "  hormons,"  in  the  blood,  arising  usually  in  one 
organ,  which  affect  the  development  of  another  organ  in  the 
body.  Starling  found  that  if  virgin  rabbits  were  given  injec- 
tions of  rabbit  embryos,  the  mammary  glands  of  these  animals 
would  hypertrophy,  and  that  the  same  substances  injected  into 
rabbits  that  had  borne  j^'oung  would  lead  to  lactation  in  addi- 
tion to  the  hypertrophy.  Loeb  has  applied  our  knowledge  of 
these  hormons  to  the  study  of  tumors  in  an  interesting  manner. 
This  author  found  that  an  injury  of  the  uterine  wall  in  a  preg- 
nant guinea  pig  would  lead  to  a  proliferation  of  decidual  tissue 
at  the  point  of  injury.  This  decidual  growth  does  not  occur, 
however,  if  the  corpora  lutea  are  removed  or  destroyed  before 
the  injury  is  inflicted.  In  other  words,  the  corpora  lutea 
apparently  form  hormons  which  stimulate  growth    of  decidula 


GAY.  67 

■tissue.  Spuda  noted  in  certain  carcinomata  that  the  growth 
of  epithelium  apparently  begins  first  about  blood  vessels,  and 
he  concludes  from  this  observation  that  there  must  be  present 
in  the  blood  stream  some  substance  which  stimulates  its  pro- 
liferation. This  supposition  of  the  presence  of  some  stimu- 
lating substance  in  the  blood  also  forms  the  basis  of  Fischer's 
theory  of  "  attraxins."  These  attraxins  are  supposedly 
-chemeotactic  substances  in  the  blood  which  stimulate  the  growth 
of  epithelial  cells.  Fischer  has  attempted  to  produce  such 
overgrowth  by  injections  of  sudan  oil,  but  offers-  no  distinct 
confirmatory  evidence  as  to  the  presence  of  such  stimulating 
substances  in  the  animal  body. 

When  we  turn  to  the  negative  physiological  influences  which 
have  been  supposed  to  contribute  to  the  growth  of  malignant 
tumors,  we  find  that  Edel  supposed  the  existence  of  certain 
normal  substances  in  the  blood  which  inhibit  epithelial  prolif- 
eration. He  would  regard  the  removal  of  these  inhibiting 
substances  as  a  primary  cause  in  the  growth  of  malignant 
tumors,  and  he  suggests  that  normal  human  serum  be  injected 
in  order  to  supply  this  deficiency.  Such  a  supposititious  lack 
of  normal  inhibiting  substances  is  comprised  in  the  theory  of 
Beard,  who  has  suggested  the  use  of  an  artificial  ferment  to 
replace  this  lacking  substance.  He  has  used  trypsin  in  human 
beings  and  claims  that  injections  of  this  substance  will  kill  the 
abnormal  tumor  cells  without  affecting  the  normal  tissue.  Von 
Leyden  and  Bergall,  who  have  attempted  to  confirm  Beard's 
results,  decided  that  no  such  effect  was  produced  by  trypsin; 
but  they,  in  turn,  describe  a  ferment  which  they  have  isolated 
from  the  liver  and  which  they  claim  affects  only  cancer  cells. 
They  attribute  the  growth  of  cancer  to  a  lack  of  this  hydrolytic 
ferment  which  is  present  in  normal  individuals. 

In  conclusion,  the  ideas  of  Albrecht  and  Ehrlich,  as  to  the 
reason  for  the  growth  of  cancer  cells  over  the  normal  cells  of 
the  body,  may  be  mentioned.  These  writers  conclude  that 
cancer  cells  grow  more  rapidly  than  normal  cells  on  account  of 
their  greater  affinity  for  nutritive  substances. 

SPONTANEOUS    CURE    OF   CANCER   IN   HUMAN   BEINGS. 

Of  great  practical  interest  in  connection  with  the  possibility 
of  producing  an  artificial  condition  of  immunitj^  in  human  beings 


68  GAY. 

afflicted  with  cancer  are  observations  on  the  disappearance  of 
both  benign  and  mahgnant  tumors  in  human  beings.  Both 
sarcomata  and  carcinomata  have  been  reported  by  Czerny^ 
Reichel,  Rotter  and  others  as  having  spontaneously  disappeared. 
As  we  shall  later  see,  the  transmissible  tumors  of  animals  fre- 
quently disappear  after  having  grown  for  a  considerable 
period  of  time. 

EMPIRICAL    ATTEMPTS    AT    SPECIFIC    TREATMENT    OF    CANCER    IN 
HUMAN   BEINGS. 

Attempts  had  been  made  to  treat  cancer  in  human  beings 
by  more  or  less  specific  methods  even  before  any  of  the  exact 
knowledge  which  has  been  acquired  from  the  study  of  experi- 
mental tumors  in  animals  was  obtained.  Busch  commented 
on  the  fact  that  the  interoccurrence  of  erysipelas  frequently 
leads  to  the  disappearance  of  cancer  in  a  patient  suffering  from 
this  disease.  On  the  basis  of  this  apparent  beneficial  effect, 
Fehleisen  treated  a  number  of  cases  of  cancer  with  cultures  of 
the  streptococcus  isolated  from  cases  of  erysipelas  and  appar- 
ently obtained  certain  beneficial  effects.  The  dangerous 
results  from  the  erysipelas  itself  led  temporarily  to  an  abandon- 
ment of  this  method  of  treatment,  but  Coley  has  for  several 
years  treated  cases  of  inoperable  sarcoma  with  a  toxin  derived 
from  the  streptococcus  of  erysipelas,  or  better  still,  with  this 
toxin  combined  with  a  toxin  from  the  bacillus  prodigiosus.  He 
has  reported  some  one  hundred  cases  of  inoperable  tumor  which 
were  either  greatly  benefited  or  apparently  perfectly  cured  by 
this  method. 

Attempts  have  been  made  to  produce  a  specific  antiserum 
for  cancer  by  immunizing  animals  with  cancer  cells.  Thus 
Richet  and  Hericourt  immunized  dogs  and  asses  with  an  ex- 
tract of  human  cancer  and  used  the  serum  of  these  immunized 
animals  in  the  treatment  of  the  disease.  Their  results  were, 
however,  uniformly  negative.  Von  Dungern's  description  of 
a  specific  epitheliolysin,  which  he  found  in  the  serum  of  rabbits 
that  had  received  injections  of  the  ciliated  epithelium  from 
the  trachea  of  the  cow,  gave  hope  of  the  possibiHty  of  forming 
such  a  specific  serum  for  other  epithelial  cells.  We  have  come, 
however,  through  the  work  of  Pearce  and  others,  to  regard 
such  cytolytic  sera  as  specific  for  the  animal  species  that  has 


GAY.  69 

furnished  the  cells  rather  than  for  any  individual  type  of  cells 
from  such  an  animal. 

THE    EXPERIMENTAL   STUDY    OF   TUMORS   IN   ANIMALS. 

Tumors  have  been  described  in  many  mammals.  In  addi- 
tion to  the  tumors  of  wild  animals,  tumors  have  been  noted  in 
such  domestic  animals  as  the  dog,  cat,  horse,  cow,  mouse  and 
rat.  Tumors  are  very  rare  in  amphibians  and  have  not  been 
described  in  reptiles.  They  do,  however,  occur  in  birds  and 
fishes.  These  tumors  of  animals  are  both  benign  and  malig- 
nant, and  the  malignant  tumors  are  characterized  by  the  same 
pecuharities  which  accompany  the  malignant  tumors  of  human 
beings. 

TRANSMISSION    OF   TUMORS    IN   ANIMALS. 

There  is  no  authentic  record  of  the  transmission  of  a  malig- 
nant tumor  in  the  human  being  to  another  individual.  There 
are,  however,  cases  in  which  tumors  have  apparently  been 
transplanted  from  one  part  of  the  body  to  another  in  a  given 
individual.  Many  attempts  have  been  made  to  transfer  the 
tumors  of  human  beings  to  animals,  and  with  a  few  exceptions 
have  been  uniformly  unsuccessful.  Dagonet  describes  the 
occurrence  of  a  tumor  growth  in  a  rat  a  year  after  implanting 
a  metatastic  tumor  from  the  lymph  gland  in  man.  Werner 
describes  the  occurrence  of  a  tumor  with  metastases  in  a  dog 
following  implantation  of  a  human  carcinoma  of  the  jaw. 
From  subsequent  observations  in  animals,  we  know  that,  as  a 
general  rule,  the  tumors  of  one  species  can  never  be  transplanted 
in  animals  of  another  species. 

Nowinski,  in  1876,  succeeded  in  transferring  a  nasal  tumor 
of  the  dog  to  another  dog.  In  1889,  Morau  transferred  a  car- 
cinoma of  the  mouse  through  seventeen  successive  generations 
in  other  mice.  In  1901,  Loeb  described  a  sarcoma  of  the  rat 
which  was  transmissible  to  other  rats  but  which  finally  died  out. 
In  the  same  year  Jensen  described  a  large  series  of  experiments 
with  a  mouse  carcinoma,  and  he  succeeded  through  a  number 
of  successive  generations  in  transplanting  his  tumor  successfully 
in  50%  of  the  animals  inoculated. 

Since  the  description  of  these  tumors,  numerous  tumors  of 
mice  and  several  tumors  of  the  rat  and  dog  have  been  described 
and  studied  by  experimental  methods.     Many  of  these  tumors 


70  GAY. 

show  the  characteristics  of  real  mahgnancy  in  that  they  pro- 
duce metastases  which  lead  to  the  death  of  the  animal. 

Spontaneous  tumors  undoubtedly  occur  much  more  fre- 
quently in  animals  than  was  at  first  suspected.  Whereas,  a  few 
years  ago,  Bashford  made  the  statement  that  spontaneous 
tumors  in  mice  occur  in  only  12  individuals  out  of  30,000, 
more  careful  observation  through  the  entire  life  history  of  these 
animals  has  led  us  to  believe  that  such  tumors  are  much  more 
common.  Tyzzer,  for  example,  has  found  that  spontaneous 
tumors  occur  in  his  mice  in  at  least  5%  of  all  the  animals.  The 
success  in  transplanting  these  spontaneous  malignant  tumors 
of  animals  varies  markedly  with  the  individual  technic  of  the 
observer.  Ehrlich  found  that  11  out  of  94  malignant  tumors 
were  transplantable.  Certain  types  of  tumors  are  much  more 
readily  transplantable  than  others.  Ehrlich  found,  for  ex- 
ample, that,  in  his  experience,  only  8%  of  the  hemorrhagic 
tumors  could  be  transmitted  to  other  animals.  That  the 
individual  technic  in  transplanting  is  a  matter  of  primary 
importance  as  to  the  percentage  in  which  these  tumors  take 
has  recently  been  evident  by  the  work  of  Gierke  and  of  Murray. 
These  authors  succeeded  in  transplanting  37  out  of  48  hemor- 
rhagic tumors  similar  to  those  described  by  Ehrlich,  They 
attribute  the  difference  in  results  to  the  fact  that  Ehrlich  used 
much  more  of  the  tumor  substance  in  transplanting  than  they 
did. 

There  are  certain  general  factors  apart  from  individual 
technic  which  must  be  considered  in  drawing  any  conclusions 
from  experiments  with  transmissible  tumors  of  animals.  There 
are  present,  indeed,  two  sets  of  varying  factors,  one  set  depend- 
ent on  the  animals  inoculated  and  the  other  on  the  tumor  used, 
for  inoculation. 

It  has  been  the  general  experience  of  workers  in  this  field 
that  young  animals  take  the  tumor  better  than  old  ones.  There 
are  very  marked  differences  between  races  of  the  same  animal 
species  in  susceptibility  to  a  given  tumor.  Thus,  Jensen  found 
that  whereas  his  tumor  took  well  in  white  mice,  it  took  in  a 
much  smaller  percentage  of  cases  in  gray  mice.  Harland  has 
found  not  only  differences  in  different  races  of  mice,  but  deter- 
mined that  a  change  of  environment  would  lead  to  a  different, 
resistance  in  a  given  race.     He  found  that  if  he  removed  Berlin. 


GAY,  71 

mice  to  Norway,  they  failed  to  take  the  Ehrlich  tumor,  whereas, 
in  Berhn,  they  were  very  susceptible  to  it.  In  addition  to 
variations  in  race  and  environment,  the  probable  differences 
in  individual  resistance  of  animals  may  be  mentioned.  The 
fact  that  certain  animals  of  a  given  lot  fail  to  take  an  implanted 
tumor,  whereas  others  do  take  it,  may  be  attributed,  as  Jensen 
has  done,  to  the  occurrence  of  a  natural  immunity  in  the  "  nega- 
tive "  animals. 

The  tumor  used  for  implantation  may  vary  remarkably  in 
"  virulence  "  during  successive  generations.  A  tumor  which 
takes  in  100%  of  cases  when  first  transplanted,  may,  after 
several  successive  generations,  take  in  only  40  or  50%.  It  is 
probable,  also,  that  individual  parts  of  a  given  tumor  vary 
in  their  virulence.  The  point  of  inoculation  of  the  tumor  is  also 
of  considerable  importance.  Thus  Bashford,  Murray  and 
Cramer  have  shown  that  if  the  tumor  is  implanted  in  the  axilla, 
many  more  animals  will  take  than  when  the  tumor  is  implanted 
on  the  dorsal  surface  of  the  animal.  This  difference  they  attrib- 
ute to  the  greater  vascularity  of  the  former  region.  We  have 
already  seen  that  variation  in  the  amount  of  tumor  inoculated 
was  the  cause  of  the  difference  in  results  between  Ehrlich  and 
Gierke  in  their  transplantations  of  hemorrhagic  tumors.  This 
factor  of  the  amount  inoculated  is  also  of  importance  in  the 
experiments  for  the  production  of  an  artificial  immunity. 
Tumors  may  change  markedly  in  cellular  type  during  successive 
generations.  Thus  Loeb,  Ehrhch  and  others  have  described 
the  transformation  of  a  carcinomatous  tumor  into  a  sarcoma, 
and  Flexner  and  Jobling  have  described  transformation  of  a 
sarcoma  of  the  rat  into  a  carcinoma.  Apolant  has  mentioned 
that  carcinomata  of  the  mouse  grown  in  partially  immunized 
animals  may  become  adenomatous  in  structure.  Such  changes 
as  these  in  cellular  type  are  of  undoubted  importance  in  the 
virulence  of  the  tumor.  The  age  of  the  tumor  is  of  some  im- 
portance in  the  percentage  of  successful  implantations.  It  is 
in  general  agreed  that  old  tumors  are  better  than  young  tumors, 
owing  perhaps  to  the  fact  that  they  contain  more  calcium. 
(Clowes  and  Baslack.)  Lewin,  by  picking  the  tumors  which 
grew  best,  succeeded  in  getting  a  more  virulent  strain.  In 
some  experiments  of  my  own,  by  successive  implantation  from 
the  metastases  of  tumors  instead  of  from  the  original  inoculated 


72  GAY. 

tumor,  I  obtained  a  tumor  which  was  more  virulent,  as  indi- 
cated by  the  fact  that  it  grew  more  rapidly  and  produced 
metastasis  sooner. 

IMMUNITY   IN    EXPERIMENTAL    CANCER. 

Jensen  attributed  the  failure  of  50%  of  his  mice  to  take  the 
tumor  to  the  existence  of  a  condition  of  natural  immunity  in 
the  negative  animals.  In  addition  to  a  failure  to  take  the 
tumor,  many  observations  have  since  been  made  as  regards 
the  resorption  of  tumors  that  were  apparently  growing  well. 
Thus,  Wehr  noted  the  spontaneous  disappearance  of  l3^mpho- 
sarcomata  in  dogs.  Gaylord  and  Clowes  found  that  20%  of 
their  apparently  successful  inoculations  in  mice  would  show 
resorption  after  a  period  of  growth.  Lewin  has  noted  similar 
results  in  connection  with  rat  tumors.  Michaelis  has  noted  the 
disappearance  of  tumors  that  have  grown  for  as  long  as  four 
weeks  in  mice. 

The  most  systematic  attempt  to  explain  this  condition  of 
natural  immunity  to  tumors  in  animals  is  the  theory  of  atreptic 
immunity  advanced  by  Ehrlich.  It  has  already  been  men- 
tioned that  the  tumor  of  one  species  will  rarely  or  never  grow 
in  an  animal  of  another  species.  Ehrlich  found  that,  although 
no  definite  growth  of  a  mouse  tumor  would  take  place  in  a  rat, 
such  an  inoculated  tumor  would  show  growth  for  about  eight 
days,  after  which  time  it  gradually  disappears.  He  found  that 
if  before  this  eight-day  period  the  mouse  tumor  which  had  been 
placed  in  the  rat  is  removed  and  reimplanted  in  a  mouse, 
vigorous  growth  took  place.  Such  a  tumor  can  be  subsequently 
reimplanted  in  another  rat  and  grown  for  a  period  of  eight 
days.  No  growth,  however,  takes  place  if  the  tumor  is  trans- 
planted from  the  first  rat  directly  to  another  rat  without  inter- 
vention of  the  mouse.  These  experiments  have  been  repeated 
and  confirmed  by  Borrell.  Ehrlich  attributes  the  failure  of 
the  mouse  tumor  to  grow  in  the  rat  to  a  lack  of  certain  "  X  " 
substances  which  are  present  in  the  mouse  and  are  necessary 
for  the  growth  of  the  tumor.  These  substances  are  not  present 
in  the  rat,  and  the  tumor  of  the  mouse  transplanted  into  this 
animal  can  grow  only  so  long  as  the  "  X  "  substances  brought 
over  mechanically  with  the  tumor  last.  After  the  exhaustion 
of  these  substances,  it  is  necessary  to  reimplant  the  tumor  in 


GAY.  73 

the  mouse  in  order  to  regain  these  particular  substances.  He 
further  presupposes  that  the  "  X  "  substances  act  either  directly 
or  indirectly  in  furnishing  nourishment  to  the  cancer  cells. 
This  theory  of  Ehrlich's  was  further  corroborated  by  his  obser- 
vations of  the  growth  of  several  tumors  along  the  line  of  inocu- 
lation. Ehrlich  found  that  on  inoculating  mice  by  a  trochar 
subcutaneously  from  the  groin  to  the  axilla  the  greatest  amount 
of  tumor  was  discharged  at  the  latter  point.  The  tumor  at 
the  axilla  then  grew  rapidly,  whereas  the  one  in  the  groin,  being 
somewhat  smaller  in  the  beginning,  soon  fell  behind  propor- 
tionately in  size.  This  failure  of  the  groin  tumor  to  grow, 
Ehrlich  attributes  to  a  monopoly  of  the  "  X "  substances 
by  the  larger  tumor  in  the  axilla.  A  third  observation  which 
contributed  to  form  his  atreptic  theory  was  that  a  second 
implanted  tumor  would  almost  never  grow  in  a  cancer  animal. 
This  latter  experiment,  as  we  shall  see  in  a  later  connection,  is 
true  only  under  certain  conditions,  and  a  consideration  of  these 
conditions  has  led  to  perhaps  the  most  interesting  results  so  far 
obtained  in  the  artificial  immunity  of  animal  tumors. 

We  may  now  consider  the  condition  of  immunity  produced 
in  mice  or  rats  which  have  resorbed  a  tumor.  Gaylord  and 
Clowes  noted  that  animals  in  which  the  tumor  had  been  resorbed 
resisted  reinoculation  with  another  tumor.  These  observa- 
tions have  been  repeatedly  confirmed  since  that  time  by  other 
observers,  the  results  differing  only  in  a  matter  of  percentages. 
It  may  in  general  be  accepted  that  animals  which  have  failed 
to  take  a  first  tumor,  or  which  have  resorbed  a  first  tumor,  will 
rarely  take  a  second  tumor;  animals  which  have  failed  to  take 
both  a  primary  and  a  second  tumor  will  practically  never  take 
a  third  tumor.  The  rat  that  was  used  in  Ehrlich's  experiments 
with  the  mouse  tumor  not  only  failed  to  allow  the  mouse  tumor 
to  grow  for  more  than  eight  days,  but  it  was  found  that  it  would 
subsequently  actually  prevent  the  growth  of  a  similar  tumor 
coming  directly  from  the  mouse  for  even  that  brief  space  of 
time.  In  other  words,  as  Ehrlich  himself  states  it,  the  rat  had 
acquired  an  active  immunity  to  the  mouse  tumor  in  addition 
to  the  atreptic  immunity  that  was  originally  present.  In  a 
similar  way  Ehrlich  found  that  animals  which  had  received 
poorly  transmissible  tumors,  and  particularly  the  hemorrhagic 
tumors  to  which  reference  has  been  made,  become  subsequently 


74  GAY. 

resistant  to  highly  transmissible  tumors.  And  in  a  similar  way 
he  found  that  animals  which  have  failed  to  take  a  moderately 
virulent  carcinoma  become  immune  not  only  to  another  im- 
plantation with  the  same  tumor,  but  also  to  implantation  with 
sarcomata.  As  a  result  of  these  observations,  he  concludes 
that  the  active  immunity  of  mice  to  tumors  is  a  pan-immunity 
rather  than  a  specific  immunity  for  any  particular  type  of  tumor. 
Other  observers  agree  more  or  less  completely  with  these  results 
and  conclusions.  It  may  be  stated  in  general  that  a  tumor 
which  fails  to  take  protects  best  against  reinoculation  with  the 
same  tumor,  but  also,  although  to  a  somewhat  less  extent, 
against  inoculation  with  another  tumor  of  different  type.  It 
has  been  noted  by  Clowes  that  living  tumor  cells  must  be  used 
to  produce  this  immunity  and  that  extractives  of  the  tumor 
itself  will  not  give  rise  to  the  condition. 

Bashford,  Murray  and  Cramer  found  that  mice  which  had 
received,  ten  days  or  two  weeks  previously,  an  injection  of  mouse 
blood  are  insusceptible  to  the  ordinary  transmissible  tumors  of 
mice.  Either  whole  blood  or  the  red  blood  cells  may  be  used 
to  produce  this  condition  or  resistance.  The  blood,  however, 
must  of  necessity  be  of  the  same  animal  species.  This  observa- 
tion has  been  confirmed  by  Lewin  in  tumors  of  the  rat.  Schone 
found  that  the  previous  injection  of  mouse  embryos  or  of  mouse 
liver  will  likewise  give  rise  to  a  condition  of  immunity  to  mouse 
tumors,  and  Bridre  found  that  the  injection  of  liver  or  spleen 
from  the  mouse  will  likewise  protect  against  mouse  tumors. 
Russell,  who  has  corroborated  these  experiments,  comes  to  the 
conclusion  that  variations  in  the  percentages  of  protection  pro- 
duced by  previous  injections  of  these  different  organs  will  of 
necessity  vary,  and  that  the  greatest  protection  is  secured  by 
the  previous  injection  of  a  tissue  the  histogenesis  of  which  is 
nearest  to  that  of  cancer  itself.  Gierke  has  tried  the  effect  of 
simultaneous  injection  of  blood  and  tumor,  but  was  not  able  to 
protect  animals  from  the  tumor  by  this  method.  In  my  experi- 
ments on  a  rat  tumor  I  have  obtained  the  same  results. 

Since  it  is  evident  from  these  experiments  that  mice  that 
have  been  previously  treated  either  with  tumor  or  with  other 
tissues  from  a  mouse  become  immune  to  inoculation  with  the 
mouse  cancer,  it  becomes  important  to  ascertain  the  exact 
nature  of  this  immunity  as  compared  with  other  known  forms 


GAY.  75 

of  immunity.  Gaylord,  Clowes  and  Bseslack  claimed  that  the 
blood  of  mice  which  had  recovered  by  resorption  of  a  tumor  had 
the  property  of  curing  mice  that  were  suffering  from  the  cancer, 
and,  when  injected  with  the  cancer,  of  preventing  the  growth 
of  the  latter.  These  experiments  have  unfortunately  never 
been  corroborated,  although  they  have  been  repeated  by  many 
experimenters.  In  my  own  experiments  I  find  that  rats  re- 
ceiving simultaneous  injection  of  the  Flexner  rat  tumor  plus 
the  blood  of  animals  that  have  received  three  or  four  implanta- 
tions of  tumor  without  any  resulting  growth  give  just  as  high 
a  percentage  of  tumors  as  do  animals  treated  with  tumor  plus 
normal  rat  blood  or  with  tumor  alone.  Throughout  my  ex- 
periments I  have  noted  the  important  variation  in  racial  sus- 
ceptibility to  the  tumor.  This  factor,  as  I  have  already  men- 
tioned, has  been  repeatedly  noted  by  other  observers  in  mouse 
tumors.  Thus,  in  my  ow^n  experiments,  whereas  the  most 
susceptible  strain  of  rats  took  the  tumor  in  100%,  rats  from 
another  dealer  took  in  only  50%,  and  animals  from  other  sources 
still  took  in  even  less  than  50%.  I  found  that  the  inoculation 
of  tumor  plus  blood  of  negative  or  refractory  animals  in  rela- 
tively susceptible  animals  gave  no  less  percentage  of  takes 
than  the  inoculation  of  tumor  alone.  In  dealing  with  animals 
from  a  markedly  insusceptible  strain,  a  curious  paradox  was 
met  with.  It  was  found  that  such  animals  would  take  in  many 
more  instances  when  they  received  the  refractor}^  blood  than 
when  they  received  tumor  alone. 

Michaelis  investigated  the  properties  of  the  blood  in  mice  that 
had  been  rendered  artificially  immune  to  mouse  tumor.  He 
found  that  the  blood  serum  of  such  animals  had  no  demon- 
strable antagonistic  property  against  cancer  cells;  that  is,  it 
failed  to  destroy  them,  and,  when  mixed  with  an  emulsion  of 
cancer  cells,  produced  no  "  reaction  of  fixation."  This  reaction 
of  fixation  is  the  most  delicate  method  at  our  disposal  for  the 
demonstration  of  anti-substances  in  the  serum  of  animals  that 
have  been  immunized  against,  or  have  reacted  to,  a  bacterial 
infection.  From  these  experiments,  then,  with  a  cancer  emul- 
sion and  serum  of  immune  animals,  we  may  conclude  that  the 
immunity  to  cancer  animals  does  not  correspond  to  the  ordinaiy 
bacterial  immunity.  These  reaction  of  fixation  experiments 
I  have  repeated  in  the  case  of  the  rat  tumor  which  I  have 


76  GAY. 

studied  and  have  also  failed  to  obtain  any  reaction  of  fixation. 
Sticker  noted  that  the  blood  of  dogs  that  had  recovered  from 
lymphosarcoma  failed  to  affect  the  cells  of  this  tumor.  Beebe 
and  Crile  have,  however,  described  certain  experiments  with 
animals  suffering  from  lymphosarcoma  which  might  seem  to 
demonstrate  the  presence  of  certain  antagonistic  properties  in 
the  blood  of  immune  animals.  These  authors  found  that  the 
transfusion  of  blood  from  a  dog  that  had  recovered  from  the 
lymphosarcoma  into  an  animal  suffering  from  the  tumor  would 
lead,  in  certain  cases,  to  a  disappearance  of  the  tumor.  These 
experiments  they  controlled  by  transfusing  the  blood  from 
normal  dogs  into  other  cases.  The  differences  seem  to  be 
marked  between  the  two  series  of  animals.  It  is,  however,  to 
be  noted  that  in  nearly  all  their  successful  experiments  more 
blood  was  transfused  into  the  cancer  animal  than  had  previ- 
ously been  removed  by  bleeding,  which  would  seem  a  factor  of 
some  importance  in  determining  the  cure. 

Bridre,  on  account  of  the  fact  that  various  mouse  tissues 
may  be  used  in  immunizing  mice  against  mouse  tumor,  has 
referred  to  this  form  of  immunity  as  an  iso-immunity  to  mouse 
tissue.  This  immunit}^,  however,  does  not  resemble  in  any 
exact  way  other  forms  of  immunity  which  have  been  described. 

As  in  the  case  of  human  beings,  many  attempts  have  been 
made,  on  more  or  less  empirical  lines,  to  produce  an  antiserum 
for  cancer  tissue.  Rabbits,  goats,  hens  and  guinea  pigs  have  all 
been  given  repeated  injections  of  mouse  tumor  and  their  sera 
have  then  been  employed  in  treating  tumors  in  mice.  The 
results  from  such  treatment  have  been,  however,  entirely 
negative. 

REIMPLANTATION  OP  TUMORS    IN    CANCER    ANIMALS    AND  A  CURE 
THROUGH   VACCINATION. 

In  spite  of  Ehrlich's  original  statements  as  to  the  monopoly 
of  food  substances,  either  by  a  larger  of  two  tumors  or  by  the 
first  tumor  when  two  are  implanted  successively,  it  has  become 
evident,  through  the  experiments  of  many  investigators,  that 
this  support  for  a  theory  of  atreptic  immunity  works  out  experi- 
mentally in  only  a  limited  number  of  cases.  It  has  been  re- 
peatedly shown  that  simultaneously  inoculated  tumors  in  a 
given  animal  will  grow  equally  well.     A  number  of  investiga- 


GAY.  77 

tors  succeeded  in  growing  a  second  tumor  in  a  cancer-bearing 
animal.  Loeb,  Bridre  and  Gierke,  indeed,  regard  the  cancer 
animal  as  a  more  favorable  soil  for  a  tumor  than  the  normal 
animal.  Schone  attempted  to  put  Ehrlich's  atreptic  theory  to 
an  experimental  proof.  He  reasoned  that  if  it  were  true  that 
the  first  implanted  tumor  monopolizes  the  nutritive  substances 
to  the  exclusion  of  a  second  implanted  tumor,  the  removal  of 
this  first  tumor  should  allow  the  second  one  to  grow.  He 
removed,  therefore,  a  tumor  that  had  been  growing  in  mice, 
and  eight  days  later  planted  a  second  tumor  and  found  that  it 
grew.  Sticker,  who  is  working  with  the  lymphosarcoma  of 
dogs,  finds  that  the  growth  of  a  tumor  in  an  animal  may  be 
divided  into  two  definite  phases.  During  the  first  phase,  which 
is  characterized  by  the  absence  of  metastasis  to  the  tumor,  the 
removal  of  the  first  tumor  is  necessary  to  allow  the  second  tumor 
to  grow.  During  the  second,  or  metastatic,  phase,  a  second 
inoculated  tumor  grows  irrespective  of  the  presence  or  removal 
of  the  primary  tumor.  Murray,  in  commenting  on  these 
experiments,  has  stated  that  reinoculation  of  the  tumor,  when 
positive,  means  that  a  metastatic  phase  is  present.  Flexner 
and  Jobling  have  repeated  these  experiments  with  the  rat 
tumor  and  have  shown  that  during  the  first  period  of  tumor 
growth  the  animal  is  protected  from  a  second  inoculated  tumor. 
Independently  of  Schone,  I  tried,  about  a  year  ago,  the 
effect  of  implanting  tumors  in  animals  from  whom  the  first 
tumor  was  removed.  Instead  of  waiting  for  eight  days,  as 
did  Schone,  I  reimplanted  the  tumor  immediately  after 
removing  the  first  tumor  and  found  that  whereas  this  second 
tumor  failed  to  take  in  tumor  animals  up  to  the  thirtieth  day 
of  growth,  it  took  in  them  from  that  period  on.  This  period  of 
thirty  days  corresponds  rather  closely  to  the  time  during  which 
no  metastases  are  evident  following  inoculation  of  this  tumor 
in  most  susceptible  animals.  In  these  susceptible  animals 
which  take  the  tumor  in  100%  of  cases,  metastases  occur  at  a 
rather  definite  period  following  implantations  of  a  uniform 
amount.  This  period  is  between  thirty  and  forty  days.  My 
results,  then,  would  agree  thoroughly  with  those  of  Sticker  as 
regards  the  separation  of  the  life  history  of  the  tumor  growth 
into  two  definite  periods,  a  pre-metastatic  and  a  metastatic 
period. 


78  GAY. 

In  some  experiments  which  were  designed  primarily  to  con- 
trol the  reimplantation  of  tumors  in  animals  from  which  the 
first  tumor  was  removed,  most  interesting  results  were  obtained. 
I  found  that  if  animals  were  given  a  second  implantation  of 
tumor  up  to  the  period  of  thirty  or  thirty-five  days,  without 
removal  of  the  'primary  tumor,  not  only  did  the  second  tumor  fail 
to  take,  but  the  first  tumor  actually  disappeared.  In  certain 
experiments,  comprising  a  number  of  animals,  the  original 
tumor  disappeared  in  nearly  every  instance.  At  later  periods 
of  time,  the  second  inoculated  tumor  grew  and  the  first  con- 
tinued to  grow.  This  type  of  experiment  has  since  been  re- 
peated a  number  of  times  with  the  additional  control  of  an 
equal  number  of  animals  in  whom  a  second  inoculation  is  not 
given  and  the  primary  tumor  simply  left.  These  control  ani- 
mals are  designed  to  show  that  the  first  tumor  does  not  spon- 
taneously resorb  in  animals  that  do  not  receive  the  second  tumor 
inoculation.  As  a  result  of  these  experiments,  I  have  found 
that  in  approximately  50%  of  the  animals  treated  during  the 
first  three  or  four  weeks  of  tumor  growth,  reimplantation  of  the 
tumor  will  lead  to  a  cure  of  the  original  tumor  and  to  a  preven- 
tion of  metastases.  The  original  tumor  usually  disappears 
under  this  treatment  within  two  weeks.  In  certain  animals 
in  whom  the  disappearance  of  the  original  tumor  is  delayed  or 
in  whom  the  cure  is  imperfect,  a  histological  study  of  the 
partially  cured  tumor  is  of  interest.  Such  tissues  show  that 
either  an  enormous  increase  of  the  connective  tissue  stroma 
has  taken  place  or  that  there  is  acute  degeneration  of  the 
epithelial  cells. 

This  cure  by  vaccination,  if  it  may  be  so  called,  corresponds 
in  many  details  to  what  we  know  of  the  treatment  for  rabies,  in 
which  instance  the  individual  may  be  treated  successfully  by 
vaccination,  that  is  to  say,  by  successive  inoculation  with  the 
virus  of  rabies,  at  anj^  time  up  to  the  third  week  following  the 
bite  of  the  rabid  animal.  The  pre-metastatic  period  in  cancer 
growth  in  animals  would  correspond,  then,  to  a  period  of  incu- 
bation, and  the  disease  itself  would  be  considered  as  declared 
only  when  metastases  appear.  These  results  in  a  treatment 
of  growing  tumors  by  reinoculation  have  been  mentioned  as 
incidental  happenings  or  have  been  indirectly  touched  upon  by 
certain  observers.     Sticker,  for  example,  mentions  that  he  was 


GAY.  79 

able  to  cure  a  sarcoma  in  dogs  at  times  by  treating  the  animals 
with  an  emulsion  of  sarcoma  cells.  Briclre  noted  a  very  unex- 
pected disappearance  of  a  mouse  tumor  in  a  few  animals  which 
had  been  treated  with  an  emulsion  of  the  tumor.  Gaylord,  on 
reinoculating  mice  every  six  days,  obtained  a  growth  of  the 
first  two  or  three  tumors,  which  tumors,  however,  after  a  period 
of  growth,  disappeared  on  subsequent  inoculation,  and  the  ani- 
mal became  immune.  In  other  words,  he  was  able  to  produce 
a  condition  of  immunity  through  vaccination  with  a  malignant 
tumor.  His  results  differ  from  my  own,  inasmuch  as  I  have 
produced  a  cure  of  a  tumor  that  has  been  growing  three  or  four 
weeks  by  a  single  reinoculation,  in  which  instance  the  reinocu- 
lation  fails  to  give  a  growth. 

Reference  has  already  been  made  to  the  failure  of  the  blood 
serum  of  animals  immunized  against  a  tumor  to  give  a  reaction 
of  fixation  with  an  emulsion  of  tumor  cells.  In  other  words, 
animals  immune  to  cancer  apparently  do  not  contain  antibodies 
to  cancer  cells  such  as  those  that  are  present  in  the  usual  bac- 
terial infections.  It  is  of  interest  to  note  that  in  the  case  of 
human  beings  suffering  from  cancer,  a  reaction  of  fixation  be- 
tween their  blood  and  cancer  tissue  has  been  proved  both  by 
Liidke  and  by  Simon  and  Thomas.  The  latter  observers  found 
a  fixation  reaction  in  65%  of  the  cancer  cases  they  examined, 
whereas  such  a  reaction  occurred  in  only  2%  of  control  normal 
individuals  or  in  cases  suffering  from  other  diseases.  These 
authors  also  mention  that  they  have  treated  some  cases  of 
cancer  with  cancer  extract.  They  do  not,  however,  state  that 
they  have  obtained  any  favorable  results.  In  my  own  experi- 
ments with  the  rat  tumor,  I  have  found  that  a  reaction  of  fixa- 
tion was  at  times  demonstrable  between  the  blood  serum  of 
cancer  rats  during  the  pre-metastatic  phase,  but  not  during  the 
metastatic  phase.  Similar  results  were  obtained  by  Clowes, 
although  he  makes  no  separation  into  metastatic  and  pre- 
metastatic  periods,  but  simply  says  that  he  obtained  a  reaction 
of  fixation  with  the  moderate  size  tumors,  but  not  with  the 
largest  tumors. 

It  would  seem  justifiable,  then,  as  a  working  hypothesis,  to 
regard  the  pre-metastatic  period  of  a  tumor  as  a  period  during 
which  the  animal  shows  reaction  products  to  cancer  tissue,  and 
during  which  period  the  animal  is  able  successfully  to  combat 


80  GAY. 

a  generalized  infection  of  the  cancer.  In  those  cases  in  which 
spontaneous  resorption  of  the  tumor  occurs,  which,  as  we  have 
alread}''  stated,  are  relatively  frequent  in  animals  and  have  also 
been  described  in  human  beings,  we  may  suppose  that  the 
resistance  of  the  individual  has  succeeded  in  overcoming  the 
cancer.  From  our  experiments  in  animals,  it  would  seem 
possible  that  during  this  pre-metastatic  reaction  period,  the 
resistance  of  the  individual  may  be  increased  by  reinoculation 
of  the  tumor,  or  possibly  of  products  of  the  tumor,  to  such  an 
extent  that  the  resorption  of  the  original  tumor  may  be  brought 
about. 


\A^: 


-^'^-xOCA/'fc'S     jC 


1 


COLUMBIA  UNIVERSITY  LIBRARIES  (hsi.stx) 

RD651H26C.1 

A  course  of  lectures  on  tumors  given  uun 


2002266504 


